# Albumin is a secret factor involved in multidirectional interactions among the serotoninergic, immune and endocrine systems that supervises the mechanism of CYP1A and CYP3A regulation in the liver

Martine Daujat-Chavanieu, Marta Kot

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Martine Daujat-Chavanieu, Marta Kot. Albumin is a secret factor involved in multidirectional interactions among the serotoninergic, immune and endocrine systems that supervises the mechanism of CYP1A and CYP3A regulation in the liver. Pharmacology and Therapeutics, 2020, 215, pp.107616. 10.1016/j.pharmthera.2020.107616. hal-04940206

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# Albumin is a secret factor involved in multidirectional interactions among the serotoninergic, immune and endocrine systems that supervises the mechanism of CYP1A and CYP3A regulation in the liver

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Martine Daujat-Chavanieu<sup>a</sup>, Marta Kot<sup>b,*</sup>

## ARTICLE INFO

Available online 24 June 2020

Keywords:

Serotonin

Albumin

Thyroid hormones

Testosterone

Inflammation

CYP isoform regulation

## ABSTRACT

This review focuses on albumin, which is involved in multidirectional interactions among the immune, endocrine and serotoninergic systems and supervises the regulation of cytochrome P450 (CYP) isoforms under conditions of both normal liver function and liver insufficiency. Special attention is paid to albumin, thyroid hormones, testosterone and tryptophan hydroxylase in these interactions as well as their potential roles in liver regeneration. The association of these factors with inflammation and the modification of the mechanism of hepatic drug-metabolizing CYP isoform regulation are also presented because changes in the expression of CYP isoforms in the liver may result in subsequent changes to a marker substance used for testing CYP activity, thus providing a simple way to control the liver regeneration process or the dangerous stimulation of hepatocarcinogenesis.

© 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## Contents

<table><tr><td>1. Introduction.</td><td>1</td></tr><tr><td>2. Albumin as a secret peripheral factor that controls the level of brain and peripheral serotonin.</td><td>2</td></tr><tr><td>3. Summary and conclusion.</td><td>9</td></tr><tr><td>References.</td><td>9</td></tr></table>

We confirm that this manuscript has not been published elsewhere and is not under consideration by any other journal.

## 1. Introduction

Serotonin (5-HT) is a well-known neurotransmitter in the brain. However, over 95% of 5-HT is synthesized outside of the brain serotoninergic system (Gershon, 2013) and plays a crucial role in liver regeneration and stimulation of hepatocarcinogenesis. In therapeutic practice, it is very difficult to identify the moment at which the serotoninergic system begins to promote cancer. It seems that the identification

of key factors involved in the interaction with the serotoninergic system will allow for the control of the liver regeneration process without the risk of stimulating hepatocarcinogenesis. Therefore, this review focuses on multidirectional interactions among the serotoninergic, immune and endocrine systems, which may change the mechanism of cytochrome P450 (CYP) isoform regulation in the liver microenvironment in the contexts of both normal liver function and liver insufficiency. It is known that a change in the mechanism of CYP isoform regulation often entails a change in the activity of CYP isoforms, which, in turn, can be easily controlled during therapy of chronic diseases and be used for safe liver diagnostics without the need for liver biopsy.

Abbreviations: AhR receptor, Aryl hydrocarbon receptor; BBB, Blood-brain barrier; CYP, Cytochrome P450 isoform; GR, Glucocorticoid receptor; 5-HTP, 5-hydroxytryptophan; IL-1β, Interleukin-1β; LAT1, L-type amino acid transporter; PXR, Pregnane X receptor; 5-HT, Serotonin; T4, Thyroxine; T3, Triiodothyronine; TPH, Tryptophan hydroxylase.

<footnote><sup>a</sup> IRMB, Univ Montpellier, INSERM, CHU Montpellier, Montpellier, France.</footnote>

<footnote><sup>b</sup> Mossakowski Medical Research Centre Polish Academy of Sciences, 02-106, Warsaw, 5 Pawińskiego Street, Poland.</footnote>

<footnote>* Corresponding author at: Department of Stem Cells Bioengineering, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, 5 Pawińskiego Street, phone: +48226685250, fax: +48 226685532, Poland.</footnote>

<footnote>E-mail address: mkot@imdik.pan.pl (M. Kot).</footnote>
The main storage sites of the body's peripheral 5-HT are platelets, in which the 5-HT concentration is approximately 25,000 - times higher than in plasma (Da Prada & Picotti, 1979). A lack of serotonin-synthesizing enzymes in platelets causes 5-HT to be actively taken up by platelets when it is released into the blood after synthesis in entero-chromaffin cells within the gastrointestinal (GI) tract (Erspamer & Asero, 1952; Gershon & Tack, 2007; Morrissey, Walker, & Lovenberg, 1977). However, there are also minor reserves of 5-HT outside the central serotonergic system, such as in lymphocytes, monocytes, macro-phages, and mast cells (Kim et al., 2010), and these cells most likely play the most important role in the process of liver regeneration. In par-ticular, hematopoietic stem cells (HSCs) have the ability to differentiate into all functional blood cells that participate in liver regeneration (Herencia et al., 2011). Nevertheless, 5-HT present outside the central nervous system has well-known beneficial and adverse effects on the liver and has a narrow therapeutic window that determines whether a regenerative process or tumor progression will occur in the liver (Essman, 1978; Lesurtel et al., 2006; Lesurtel, Soll, Graf, & Clavien, 2008), Matondo et al., 2009, Mercado, Ziu, & Kilic, 2011, Padickakudy et al., 2017, Kot & Daujat-Chavanieu, 2018).

The substrate for 5-HT synthesis is tryptophan, which is an essential amino acid that must be derived from the diet (Fernstrom & Wurtman, 1971). It is noteworthy that the therapeutic effects of some antidepressant drugs, which are dependent on the brain 5-HT content, positively correlate with plasma levels of tryptophan (Delgado et al., 1990). In addition, an extreme reduction in tryptophan in the diet results in a significant mood reduction (Young, 1991). Therefore, it would seem that the consumption of tryptophan-rich foods (such as bananas or chocolate) can easily increase the level of tryptophan in the blood and finally the level of 5-HT in the brain, leading to an improvement in mood or an increased the level of 5-HT in the blood, leading to hyperserotonemia. However, an increase in plasma and brain tryptophan levels as well as in levels of 5-hydroxytryptophan (5-HTP), 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) is observed for only 10 to 60 min after the injection of L-tryptophan (Carlsson & Carlsson, 1988; Fernstrom & Wurtman, 1971). In addition, surprisingly, these levels never exceed the concentrations that occur nocturnally in untreated animals as result of their normal 24-h rhythms (Fernstrom & Wurtman, 1971). In addition, improving mood by eating foods rich in tryptophan, such as chocolate, is rather fleeting (Parker, Parker, & Brotchie, 2006). Moreover, the consumption of tryptophan-rich food does not lead to autism, although a higher level of 5-HT is often observed in the blood of autistic patients (Muller, Anacker, & Veenstra-VanderWeele, 2016), and tryptophan depletion exacerbates some symptoms characteristic of autism in patients with autistic disorder (McDougle et al., 1996).

Collectively, all these associations suggest the presence of fast-acting peripheral factors that control the availability of tryptophan and thus play a key role in the control of the brain and peripheral 5-HT levels.

## 2. Albumin as a secret peripheral factor that controls the level of brain and peripheral serotonin

Given that tryptophan, unlike other amino acids, is 80-90% bound to albumin, the transport of tryptophan into the brain is strictly controlled by the albumin that binds the free plasma tryptophan (Pardridge, 1979). Albumin is exclusively synthesized by hepatocytes and is subject to self-regulation (Arroyo, García-Martinez, & Salvatella, 2014) because hypoalbuminemia stimulates albumin synthesis, while albumin infusion depresses albumin synthesis. Perturbation of the mechanism of the self-regulation of albumin concentration in the plasma may lead to low levels of serum albumin. Notably, tryptophan limitation is correlated with a decrease in albumin nuclear transcript abundance, and this decrease precedes the decrease in albumin mRNA (Marten, Burke, Hayden, & Straus, 1994). It would seem that this phenomenon can explain why higher mortality during hospital stay is directly associated with low levels of serum albumin (Iwata, Kuzuya, Kitagawa, & Iguchi,

2006), which are positively correlated with lower levels of serum tryptophan (Maes et al., 1997).

The following studies demonstrated that the downregulation of albumin gene expression is observed in the context of both normal liver function and liver insufficiency after tryptophan is reduced in the diet, and this, in turn, suggests the presence of physiological cross-talk between the expression of albumin and the serum tryptophan level responsible for the control of liver synthesis (Kot & Daujat-Chavanieu, 2016; Kot & Daujat-Chavanieu, 2018). A similar correlation between the levels of albumin and L-tryptophan is observed in depressed patients. A lower L-tryptophan availability in the brain in individuals with depression is related to lower serum albumin (Maes et al., 1996; Maes et al., 1997), whereas a significantly decreased risk of depression is observed among men and women with the highest serum albumin levels (Poudel-Tandukar, Jacelon, Bertone-Johnson, Palmer, & Poudel, 2017). Note that only the dissociation of tryptophan from albumin causes a sustained increase in 5-HT synthesis in the brain because in tissues such as the liver, the rate of tryptophan metabolism is increased after the displacement of albumin-bound tryptophan (Salter, Knowles, & Pogson, 1989). On the other hand, the binding of plasma albumin to tryptophan inhibits the blood-brain transfer of tryptophan in an inverse proportion to the plasma free tryptophan concentration (Takada, Grdisa, Diksic, Gjedde, & Yamamoto, 1993). Thus, these studies confirm that a long-term strategically important physiological factor that controls the level of 5-HT in the brain and periphery is located beyond the brain. Albumin fits perfectly in this role, especially because albumin binds plasma free tryptophan and controls the transport of tryptophan into the brain (Fig. 1).

Surprisingly, a seemingly contradictory relationship is observed in autistic people in the form of an increase in serum albumin together with an increase in 5-HT level (Burgess, Sweeten, McMahon, & Fujinami, 2006; Croonenberghs et al., 2002). This discrepancy focuses on the tertiary structure of albumin because any changes in the conformation of albumin can lead to turnoff mechanism of the self-regulation of albumin concentration. Altered conformation of albumin may be responsible for decreased binding of tryptophan in the plasma, which ultimately results in higher levels of serum 5-HT despite the same level of albumin. Additionally, it seems that alterations in the conformation of serum albumin may be a mechanism to control the tryptophan level in the brain and may be able to explain the inverse correlation between a high serotonin level in the plasma and low serotonergic neurotransmission in the brains of autistic patients.

The observation that an excess level of copper (Cu), an important mediator of free radical toxicity, is commonly diagnosed in autistic patients (Bjorklund, 2013) additionally confirms the possibility of a pathological conformation of albumin. In the plasma of healthy individuals, a high percentage of copper (Cu) is bound to albumin (Halliwell, 1988), which protects the cells from biological damage by the deleterious hydroxyl radical formed during the reaction of free Cu(II) cations with hydrogen peroxide ($H_2O_2$), known as the Fenton reaction.

At this point, the question arises: what can control the structure and conformation of albumin under physiological and pathophysiological conditions and, as a result, influence the level of serotonin?

### 2.1. An interaction of albumin with thyroid hormones

Thyroid dysfunction is frequently found in autistic patients (Kahn, 1970). Note that albumin is one of the transfer proteins for thyroxine (T4) (Schussler, 2000). A reduced rate of albumin synthesis and catabolism, an increased transcapillary escape rate of albumin, and a marked increase in the extravascular mass of albumin are observed in patients with hypothyroidism (Parving et al., 1979). Moreover, hypothyroidism is more prevalent in patients with hepatocellular carcinoma (Reddy et al., 2007), while the increased parameter measures of HCC aggressiveness correlate with low serum albumin levels (Carr & Guerra, 2017).
Thus, thyroid hormones can interfere with the level and structure of albumin, but the question is how.

### 2.1.1. *The first option: a protective role of thyroxine*

T4 is essential for increasing the rate of glucose turnover (Müller, Paschen, & Seitz, 1983). In turn, serum glycated albumin (GA), a short-term marker of glycemia (Freitas, Ehlert, & Camargo, 2017), is elevated in the hypothyroid state and reduced in nondiabetic patients with thyrotoxicosis (Koga, Murai, Saito, Matsumoto, & Kasayama, 2009). Taken together, these results suggest that it is very possible that thyroxine plays a protective role by masking the glycation sites of albumin when binding to albumin because the glycation of albumin can lead to the rearrangement of amino acids in the tertiary albumin structure and may perturb the mechanism of self-regulation of albumin concentration in the plasma.

### 2.1.2. *The second option: an interference between the expression of L-type amino acid transporter LAT1 and thyroid hormones*

Several functional mutations in the solute carrier transporter 7a5 (Slc7a5) gene coding the L-type amino acid transporter LAT1 have been identified in autistic patients (Tärlungeanu et al., 2016). The L-type amino acid transporter LAT1 is a transmembrane protein that is selectively expressed at the blood-brain barrier (BBB) that ensures the

transport of tryptophan from the blood to the brain (Boado, Li, Nagaya, Zhang, & Pardridge, 1999). However, LAT1 is also a secondary thyroid hormone transporter, which can transport thyroid hormones (Friesema et al., 2001; Morimoto et al., 2008). Thus, the changes in the expression of LAT1 may disrupt the *steady state* of thyroid hormones, which controls the conformation of albumin. This mechanism is not yet known. Nevertheless, the overexpression of LAT1 observed in hepatocellular carcinoma (HCC) (Namikawa et al., 2015) supports this hypothesis because it can supply tumor cells with the thyroid hormones necessary to control albumin synthesis and structure. Thus, the overexpression of LAT1 appears to be a “Trojan horse” in cancer cells and to stimulate tumor cell growth. On the other hand, it is worth mentioning that hypothyroidism is associated with poorer overall and recurrence-free survival among HCC patients receiving liver transplantation (Zhang et al., 2018) and is also associated with a significantly increased risk of HCC among women (Hassan et al., 2009) and liver cancer in general among patients with no known underlying cause of liver disease (Reddy et al., 2007). Therefore, downregulation of LAT1 expression focused on only cancer cells may play a beneficial role during liver cancer therapy.

### 2.1.3. *The third option: an interference with thyroxine during inflammation*

In the brain, 80% of T3 is produced locally by type 2-deiodinase (D2) activity from T4 (Bernal, 2005; Crantz, Silva, & Larsen, 1982) and is

<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Albumin, a secret factor involved in multidirectional interactions among the serotoninergic, immune and endocrine systems.</figcaption></figure>
maintained within narrow limits by a mechanism involving D2 and type 3-deiodinase (D3) activity, the T3-inactivating enzyme (Bernal, 2005). Note that the induction of a systemic acute-phase response by lipopolysaccharide (LPS) is associated with elevated levels of interleukin (IL)-1β and IL-6 (Chen et al., 2008), increased D2 and decreased T3-inactivating enzyme (T3) expression in the brain (de Vries et al., 2019). Thus, neuroinflammation in the brain leads to the disruption of thyroid hormone homeostasis and decreases the level of T4 by stimulating T3 hormone production. In turn, hypothyroidism, which is characterized by a low level of T4, is in line with the perturbation of the self-regulatory mechanism of albumin levels in the plasma. This correlation is frequently observed in autistic patients (Croonenberghs et al., 2002; Kahn, 1970). It would seem that this correlation can explain, to some extent, a lack of therapeutic benefits of antidepressant treatment associated with increased levels of proinflammatory-cytokines, which is sometimes observed in individuals with depression (Strawbridge et al., 2015). In particular, increased secretion of proinflammatory-cytokines, mainly IL-1β, which is an important mediator of the inflammatory response, correlates with the downregulation of liver albumin gene expression (Maes, 1995; Maes et al., 1997; Moshage, Janssen, Franssen, Hafkenscheid, & Yap, 1987). Moreover, controlling the thyroxine-albumin interaction may help provide a faster noninvasive diagnosis of HCC, thereby increasing survival in patients suffering from HCC. Aberrant immune responses are linked with HCC (Budhu & Wang, 2006).

On the other hand, a surprisingly different situation occurs in familial dysalbuminemic hyperthyroxinemia in which an elevated T4 level and normal thyroid stimulating hormone (TSH) and T3 levels are characteristic, while the serum albumin level is quantitatively normal (Hennemann et al., 1979). Nevertheless the structure of the albumin molecule is abnormal and determines an increased affinity for serum thyroxine. It is known that familial dysalbuminemic hyperthyroxinemia usually does not require treatment. Thus, this association suggests that an elevated level of T4 and its binding to serum albumin is not sufficient to result in pathological changes in the level of serotonin. In other words, a high level of T4 seems to be safe.

Nevertheless, it is important to note that human serum albumin contains a single tryptophan residue at amino acid position 214, and the albumin-thyroxine interaction significantly influences the albumin-tryptophan interaction (Dughi, Bhagavan, & Jameson, 1993; Steiner, Roth, & Robbins, 1966). On the other hand, the presence of tryptophan at position 214 does not appear to favorably influence the binding of T4 to serum albumin under physiological conditions (Petersen, Ha, Harohalli, Park, & Bhagavan, 1997). Therefore, it is possible that the absence of the binding of thyroxine to serum albumin can indirectly control the increase in 5-HT level both in the brain and periphery by preventing the interaction between albumin and tryptophan and the release of tryptophan into serum. The observed downregulation of albumin gene expression in parallel with a decrease in thyroxine and serum 5-HT levels in the context of liver insufficiency after reducing tryptophan in the diet, as well as an increase in serum 5-HT level in parallel with a decrease in thyroxine level in the context of liver insufficiency before reducing tryptophan in the diet, confirms both the occurrence of such an effect and an important role of the interaction between thyroxine and serum albumin for normal liver function (Kot & Daujat-Chavanieu, 2016; Kot & Daujat-Chavanieu, 2018).

The question arises regarding whether it is possible to control the above observed interaction to capture this critical point between the normal liver function and liver insufficiency and to control the liver regeneration process without the risk of stimulating hepatocarcinogenesis (Table 1).

2.1.3.1. An interference albumin with thyroxine and albumin with tryptophan supervises the mechanism of CYP1A regulation in the liver. Serotonic system dysfunction caused by the reduction in tryptophan in the diet in the context of liver insufficiency is associated with a decrease in T4 levels in parallel with aryl hydrocarbon receptor (AhR) activation

<table><caption>**Table 1**
The attack and defense mechanism after serotonergic system dysfunction.</caption><thead><tr><th colspan="3">The attack and defense mechanism after serotonergic system dysfunction</th></tr></thead><tbody><tr><td>Thyroid hormones</td><td>Markers of healthy liver function</td><td>Risk markers of liver insufficiency</td></tr><tr><td>Triiodothyronine (T3)</td><td>downregulation of T3<br>unknown mechanism:<br>upregulation of CYP3A and PXR</td><td>upregulation of T3 and proinflammatory cytokines<br>downregulation of albumin and HNF4<br>unknown mechanism:<br>upregulation of TRα1 with downregulation of CYP3A and PXR</td></tr><tr><td>Thyroxine (T4)</td><td>upregulation of T4,<br>unknown mechanism:<br>upregulation of CYP1A2;<br>masking the glycation sites of albumin;</td><td>upregulation of CYP1A1, CYP1B1 and AhR (a unique target for therapeutic immuno-modulation).<br>downregulation of albumin, T4 and CYP1A2<br>unknown mechanism: the changes in the expression of LAT1 that disrupt the steady state of thyroid hormones, which controls the conformation of albumin</td></tr></tbody></table>

and UGT1A isoform upregulation (Kot & Daujat-Chavanieu, 2016). It is known that the stimulation of glucuronidation as a consequence of AhR receptor activation may lead to reduced T4 levels (Wu, Green, Huang, Hays, & Chopra, 2005). Conversely, down-regulation of AhR mRNA associated with downregulation of the AhR target gene UDP-glucuronosyltransferase (UGT1A) may lead to an increase in plasma T4 levels (Yanagiba et al., 2008).

The AhR receptor affects the proliferation, tissue invasion, metastasis and angiogenesis of cancer cells in different types of cancer (Dietrich & Kaina, 2010) and is a unique target for therapeutic immunomodulation (Quintana, 2013). Moreover, the AhR plays a critical role in carcinogenesis since it also functions as a transcriptional regulator of phase I metabolism gene expression (CYP1A1, CYP1A2 and CYP1B1) (Shimizu et al., 2000; Nakatsuru et al., 2004) along with the previously mentioned control of UGT1A gene expression belonging to phase II.

In general, the AhR receptor controls the balance between activation of procarcinogens into DNA-reactive metabolites and their detoxication. For example, CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer-preventative activity (Androutsopoulos, Tsatsakis, & Spandidos, 2009). CYP1B1 has important implications for tumor development and progression and the development of anticancer drugs specifically activated by CYP1B1 because is overexpressed in tumor cells (Murray, Melvin, Greenlee, & Burke, 2001). Moreover, both CYP1A1 and CYP1B1 are mainly extrahepatically expressed (Zanger & Schwab, 2013), while their inducible gene expression in the liver is only regulated in response to inducers of the AhR receptor.

However, a key piece of information is that both the constitutive and inducible expression of CYP1A2 is restricted only to the liver. Studies in mice lacking the AhR receptor confirm that the constitutive gene expression of CYP1A2 is AhR-independent, while the inducible gene expression of CYP1A2 is regulated only in response to inducers of the AhR receptor (Mimura et al., 1997; Lahvis & Bradfield, 1998). One of the endogenous ligands/inducers of the AhR is kynurenine, a tryptophan metabolite that promotes mast cell activation through the AhR receptor (Kawasaki et al., 2014). This effect has been shown in both mouse bone marrow-derived cultured mast cells (BMMCs) from AhR-null (AhR KO) mice and human peripheral blood-derived cultured mast cells (HCMCs). Similar situations are observed during cancer progression and inflammation in the local microenvironment, when kynurenine is produced in amounts sufficient to activate the AhR receptor (Opitz et al., 2011).
Interestingly, superinduction of the CYP1A1, CYP1B1 and UGT1A genes with a concomitant increase in the protein expression and activity of CYP1A1 following activation of the AhR receptor in parallel with downregulation of the CYP1A2 gene, protein expression and activity was observed during liver insufficiency after dysfunction of the serotonergic system caused by a removal of tryptophan from the diet (Kot & Daujat-Chavanieu, 2016). In turn, in another study, integrative measurements of CYP1A2 activity along with the brain and peripheral 5-HT levels after selective depletion of the brain 5-HT level by administration of PCA (*p*-chloroamphetamine) and PCPA (*p*-chlorophenylalanine), as well as brain and peripheral 5-HT levels following administration of a tryptophan-deficient diet, confirmed that the dysfunction of the serotonergic system is associated with an increase in CYP1A2 activity in the context of normal liver function (Kot & Daniel, 2011; Kot & Daujat-Chavanieu, 2016; Kot & Daujat-Chavanieu, 2018; Kot, Pilc, & Daniel, 2012). Thus, the serotonergic system dysfunction stimulates both constitutive and inducible CYP1A2 expression during normal liver function. In turn, inducible CYP1A2 expression is ineffective during liver insufficiency after dysfunction of the serotonergic system (Kot & Daujat-Chavanieu, 2016). The different regulation of CYP1A1 (regulation only AhR-dependent) and CYP1A2 (regulation both AhR-dependent and AhR-independent) isoforms is a very good explanation of this phenomenon and was suggested in our paper (Kot & Daujat-Chavanieu, 2016). These genes are located very close to each other on the same chromosome and are oriented in opposite directions with respect to each other (Corchero, Pimprale, Kimura, & Gonzalez, 2001). Moreover, it seems that inducible CYP1A2 expression cannot exist without proper constitutive CYP1A2 expression, which is controlled by the serotonergic system.

Interestingly, based on the above-mentioned associations, we assert that the interplay of albumin with thyroxine is a defensive mechanism that is activated during normal liver function and is inactivated during liver insufficiency after dysfunction of the serotonergic system. It seems that this defensive mechanism supervises the induction of CYP1A2 after serotonergic system dysfunction. Of course, further studies are necessary to confirm the functionality of this mechanism, but an increase in the serum concentration of thyroxin after administration of PCPA (Masalova & Sapronov, 2009) as well as an induction of CYP1A2 activity after administration of PCPA (Kot & Daniel, 2011) measured as the rate of CYP isoform-specific and species-specific reactions (Kot & Daniel, 2008c; Kot & Daniel, 2008b; Kot & Daniel, 2008a) strongly support its existence.

Taken together, these studies suggest that the increase in CYP1A2 activity in patients after dysfunction of the serotonergic system may be a marker of healthy liver function that allows for the control of the liver regeneration process without stimulation of hepatocarcinogenesis since CYP1A2 is a liver-specific isoform, and constitutive gene expression of this isoform is under control of the serotonergic system engaged in both liver regeneration and the stimulation of hepatocarcinogenesis. Of course, further studies are necessary to confirm this observation. Nevertheless, this phenomenon is worthy of attention because the measurement of CYP1A2 activity after dysfunction of the serotonergic system could be a very helpful and practical tool to assess health during the functional recovery of the liver in both the donor and the recipient after surgery.

Moreover, these results confirm the presence of an important link between AhR receptor activation and the silencing of the interaction between thyroxine and albumin. These latter effects may result in the release of tryptophan into serum and, finally, an increase in the 5-HT level. A more complete understanding of this mechanism is yet to come.

Overall, these associations confirm that albumin plays a key role in the stimulation of 5-HT synthesis while T4 protects the structure and conformation of albumin from destabilization by misfolding and suggest that stimulation of T4 production may be a safe way to support the regeneration process in the liver.

### 2.1.4. The fourth option: an interference with triiodothyronine (T3) during inflammation

It is known that triiodothyronine-activating enzyme D2 in the basal state is expressed in the brain, but the upregulation of D2 expression is also observed in the liver during the initiation phase of inflammation (Kwakkel, de Vries, Stap, Fliers, & Boelen, 2014), and locally produced T3 may play a beneficial role in the treatment of diseases associated with liver insufficiency. The observation that T3 accelerates the differentiation of rat liver progenitor cells into hepatocytes (László et al., 2008) supports the above conclusion. Additionally, note that both acute (as measured by mitotic count, proliferating cell nuclear antigen (PCNA), and cyclin expression) and late regeneration (as measured by the complete normalization of liver histology) which are 5-HT dependent (Lesurtel, Soll, & Humar, 2012), occur in D3-deficient hepatocytes (Castroneves et al., 2014). It is known that T3 that is locally produced during inflammation can bind the thyroid hormone (TR)α1 receptor (Kwakkel et al., 2014). However, a more recent study suggested that the stimulation of the TRα1 receptor by T3 may not be possible in the context of liver insufficiency because a decrease in the level of serum tryptophan (a well-known marker of an immune-inflammatory response in individuals with depression) leads to the upregulation of TRα gene expression with a concomitant increase in the protein levels of both alternative spliced isoforms of TRα, especially the TRα2 isoform, which has no hormone-binding domain (Kot & Daujat-Chavanieu, 2016). Moreover, peripheral D3 expression is often reactivated in injuries, and a large induction of hepatic D3 expression and activity is observed after partial hepatectomy (Kester et al., 2009). In turn, upregulation of D3 expression is correlated with decreased serum and liver T3 and T4 levels (Kester et al., 2009). Furthermore, studies based on conditional knockout mice with targeted deficiency of D3 only in hepatocytes showed that the injury-induced expression of D3 in peripheral tissues is an important determinant of low T3 syndrome (Castroneves et al., 2014), which is observed in up to 75% of hospitalized patients (Huang & Bianco, 2008). It is known that T3 levels negatively correlate with serum albumin in liver diseases (Manka et al., 2019); thus, a low level of T3 seems to promote the healing process and should be expected during liver regeneration.

Given that an altered cytokine profile is associated with dysfunction of the serotonergic system during liver insufficiency (Kot & Daujat-Chavanieu, 2018), so an increased secretion of proinflammatory cytokines may be an important signal to stop the liver regeneration process. Inflammation leads to a decrease in the expression of both primary thyroid hormone transporters and LAT1 (Wittmann, Mohácsik, Balkhi, Gereben, & Lechan, 2015), which can limit the thyroid hormone supply.

#### 2.1.4.1. An interplay of albumin with triiodothyronine (T3) and albumin with tryptophan can supervise the mechanism of CYP3A regulation in the liver
The upregulation of TRα gene expression with a concomitant increase in the protein levels (Kot & Daujat-Chavanieu, 2016) may be important for an interaction of the TRα-receptor with the pregnane X receptor (PXR) transcription factor, which is involved in the regulation of CYP3A isoforms after serotonergic system dysfunction. This mechanism is not yet known. However, a repressive role of TRα1 in CYP3A4 regulation associated with the ratio PXR/TRα1, which correlates with basal CYP3A4 expression (Istrate, Nussler, Eichelbaum, & Burk, 2010) and a decrease HNF4α protein level (Kot & Daujat-Chavanieu, 2016) as well as downregulation of PXR, with concomitant decreases in the gene expression, protein level and activity of the CYP3A2 isoform (Kot & Daujat-Chavanieu, 2018) observed after serotonergic system dysfunction during liver insufficiency, strongly support the existence of such a mechanism under control of the serotonergic system.

### 2.2. An interaction of albumin with testosterone

Testosterone (T) circulates in plasma nonspecifically bound to albumin, and bioavailable T increases proportionately with increases
in free and albumin-bound T (Manni et al., 1985). Note that the binding of testosterone to albumin is higher ($K_{25\text{C}} = 2.38 \times 10^4$ l per mole for testosterone by albumin) than the binding of albumin to L-tryptophan ($K_{25\text{C}} = 1.6 \times 10^4$ liter per mole for L-tryptophan by albumin), which is only one amino acid that reversibly binds albumin (Kragh-Hansen, 1981; McMenamy & Oncley, 1958; Vermeulen & Verdonck, 1968). Thus, these properties may be responsible for higher levels of plasma free tryptophan in males than in females (Nishizawa et al., 1997).

Interestingly, the growth of vocal control nuclei of adult male European starlings exhibits plasticity associated with seasons, and their volume is larger under a spring-like (long) photoperiod, when testosterone levels and song production are high, than under a winter-like (short) photoperiod, when testosterone levels and vocal output are low (Nottebohm, 1981; Absil, Pinxten, Balthazart, & Eens, 2003). It is worth noting that Reelin which is expressed in the high vocal center, decreased with high plasma testosterone levels (Absil et al., 2003). The perturbation of canonical Reelin signaling is also associated with the dysregulation of 5-HT signaling during critical periods, as observed in autism (Shehabeldin et al., 2018). Furthermore, expression of Reelin, a functional protein, is observed during some phases of liver fibrosis, which are serotonin-dependent and associated with liver injury, (Carotti et al., 2017).

Thus, there is an interplay between testosterone level and the functioning of the serotonergic system; how this interplay looks remains to be defined.

### 2.2.1. *An interference of testosterone with tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of 5-HT from tryptophan in the brain and periphery*

Tryptophan hydroxylase (TPH) is the first and rate-limiting enzyme in the synthesis of 5-HT from the 5-HT precursor tryptophan to 5-HTP, and it is important that it exists in two isoforms: tryptophan hydroxylase 1 (TPH1) and tryptophan hydroxylase 2 (TPH2) (Matthes & Bader, 2018; Sakowski et al., 2006; Walther et al., 2003; Walther & Bader, 2003).

The TPH1 isoform is found in the pineal gland (the place of melatonin synthesis) (Nakamura & Hasegawa, 2007), thymus, spleen and gut, while the TPH2 isoform is selectively expressed in the brain, with small exceptions, such as neuron-containing layers of the intestine (Neal, Parry, & Bornstein, 2009) and nonneuronal sites (islets of Langerhans in pregnant females (Rieck et al., 2009; Schraenen et al., 2010).

Interestingly, TPH1 has stronger enzymatic activity than TPH2 (McKinney, Knappskog, & Haavik, 2005; Nakamura & Hasegawa, 2007) and may also play a critical role in hormonal imprinting during seasons, diurnal rhythm or pregnancy. Conversely, tryptophan hydroxylase isoform 2 (TPH2), encoded by the *Tph2* gene, is involved in the regulation of aggressive behavior (Kulikov, Osipova, Naumenko, & Popova, 2005; Popova, 2006). Many studies in psychopaths and/or criminal samples combined aggressive behavior with a higher testosterone level (Stälenheim, Eriksson, von Knorring, & Wide, 1998). Serotonin turnover is decreased in isolated, aggressive mice, while isolation-induced aggression in mice can be selectively antagonized by either serotonin receptor blockade or depletion of serotonin via synthesis inhibition with PCPA (*p*-chlorophenylalanine) (Malick & Barnett, 1976). Interestingly, long-term deficiency of tryptophan from the diet in the context of liver insufficiency increased the level of testosterone and decreased the level of protein kinase A (PKA) compared with those observed in animals following induced dysfunction of the serotonergic system during normal liver function (Kot & Daujat-Chavanieu, 2018). In turn, the 5-HT1A and 5-HT1B agonists completely inhibit aggressive behavior, irrespective of their intrinsic activities, while the 5-HT2 agonist DOI has an antiaggressive effect only at high doses, whereas the 5-HT2 antagonist ritanserin and the 5-HT3 antagonist ondansetron are ineffective (Sánchez, Arnt, Hyttel, & Moltzen, 1993; De Boer & Koolhaas, 2005). Moreover,

testosterone deprivation due to gonadectomy in male animals leads to an increase in serotonin (5-HT) release (Knoll, Miklya, Knoll, & Dalló, 2000) and the upregulation of *5-HT1A* (Zhang, Ma, Barker, & Rubinow, 1999), *5-HT2A* and *SERT* gene expression in the brain (Sumner & Fink, 1998).

It is worth noting that testosterone secretion in the male rat is high during the late fetal and immediate postnatal periods, and a rapid decrease 3 h after birth is then observed, which remains low until puberty (Gogan, Slama, Bizzini-Koutznetzova, Dray, & Kordon, 1981).

Information that perinatal testosterone is engaged in the development of sexually dimorphic behaviors (Shapiro, Levine, & Adler, 1980; Feder, 1981) seems also to be very important in the context of autism development. In particular, a period of high brain serotonin synthesis capacity during childhood is disrupted in autistic children (Chugani et al., 1999). Brain imaging studies used positron emission tomography to confirm that young children with autism lacked the developmental peak in brain 5-HT synthesis capacity seen in typically developing infants (Pardo & Eberhart, 2007). Given that serotonin has an impact on male sexual behavior, which is strictly testosterone (T) -dependent, the irreversible imprinting effects of neonatal androgen treatment may play a key role in the development of autism.

It is worth noting that hyperserotonemia of autism is more prevalent in prepubertal than postpubertal autistic patients (MCBRIDE et al., 1998) and may be heterogeneous, with one subgroup of subjects with increased platelet 5-HT uptake and another subgroup with decreased 5-HT2 binding (McBride, 1989; Cook et al., 1993).

Administration of specific agonists for the receptors 5HT<sub>1/7</sub> (5-CT, 5-carboxyamidotryptamine maleate), 5HT<sub>2A</sub> (DOI, 2,5-dimethoxy-4,5-iodoamphetamine hydrochloride) and 5HT<sub>2B</sub> (alpha-Me-HTP, a-methyl-5-hydroxytryptamine maleate) into Huh7 and HepG2 cells revealed that only the 5HT2B receptor is a mediator of survival and that 5-HT mediates the proliferation of human hepatocellular cancer cells as a result of cytoprotection (Soll et al., 2010). Moreover, it was observed that the 5HT2B receptors were a molecular target of HCC in animal models of HCC, including athymic mice treated with the 5HT2B receptor antagonist SB204741 and CCL4-treated mice lacking peripheral 5-HT due to a deletion of TPH1 (Soll et al., 2010). Unfortunately, 5-HT2B receptor-based therapy has some limitations. Genetic ablation of 5-HT2B leads to embryonic and neonatal death caused by heart defects (Nebigil et al., 2000). In turn, stimulation of 5-HT2B receptor signaling results in reduced blood vessel lumen diameter and increased vascular resistance (Esteve, Launay, Kellermann, & Maroteaux, 2007). Much more interesting in the context of liver regeneration is the observation that hypoxic mice with genetically or pharmacologically inactive 5-HT2B receptors do not develop pulmonary artery hypertension (PAH) because the 5HT2B receptor is a limiting step in the development of PAH (Launay et al., 2002). It is known that patients with advanced liver disease often have pulmonary hypertension (Bozbas et al., 2009). Therefore, overall, the suppression of 5-HT2B receptors is useful only during the process of liver regeneration.

Interestingly, short-term deficiency of tryptophan from the diet in the context of liver insufficiency was sufficient to observe the suppression of 5-HT2B receptors and the accompanying downstream effects (Kot & Daujat-Chavanieu, 2016). The activation of protein kinase C (PKC) was not lost at this time. Moreover, a significant increase in vascular endothelial growth factor (VEGF) level was noted after serotonergic system dysfunction in the context of liver insufficiency and confirmed the possible indirect activation of the 5HT2A receptor despite the absence of serotonin (Kot & Daujat-Chavanieu, 2016). It is known that 5-HT can stimulate the same signaling pathway that is activated by VEGF (Zamani & Qu, 2012). Thus, stimulation of the signaling pathway associated with PKC can be an important stage during liver regeneration in patients with liver insufficiency. Specifically, selective activation of VEGF receptor-1 (VEGFR-1) stimulates hepatocytes *in vivo* and reduces liver damage in mice exposed to hepatotoxins, and exogenous VEGF stimulates liver regeneration following partial hepatectomy (Phx) (Kraizer et al., 2001; LeCouter et al., 2003).
Collectively, the results of the above studies confirm that the inter-
play between the level of testosterone and the functioning of the sero-
tonergic system play critical roles in the development of autism and
liver insufficiency induction. At this point, the main question is how to
control this interaction (Fig. 2A and B).

2.2.1.1. An interplay between testosterone and the serotonergic system su-
pervises the mechanism of CYP1A and CYP3A regulation in the liver.
Chronic administration of most antidepressants reduces the quantity
of 5-HT2 binding sites (Kendall, Stancel, & Enna, 1982). Castration abol-
ishes the decline in the concentration of 5-HT2 brought on by chronic
imipramine treatment in both male and female rats, while the receptor
response to trazodone was not influenced by castration (Kendall et al.,
1982). Interestingly, testosterone and estrogen, but not dihydrotestos-
terone, reversed the effects of castration in males (Kendall et al.,
1982). This action of testosterone depends upon its conversion to estro-
gen by aromatase because this effect was not mimicked by 5α-
dihydrotestosterone (5α-DHT) (Kendall et al., 1982; Sumner & Fink,
1998). It should be noted that CYP1A2 is the major enzyme involved
in the metabolism of imipramine (Brøsen, 1995), while trazodone is a
substrate for CYP3A4 (Rotzinger, Fang, & Baker, 1998).

Interestingly, testosterone can stimulate the expression of AhR and its interaction with the androgen receptor (AR), leading to the stimulation of LRH-1 gene expression (the expression of the liver receptor homolog 1 (LRH-1)) (Wu, Baumgarten, Zhou, & Stocco, 2013). These effects are not mimicked by 5α-dihydrotestosterone (5α-DHT) (Wu et al., 2013). However, an inhibition of AhR-dependent genes, both CYP1A1 and CYP1A2 isoforms, by physiological levels of androgen observed in Meishan pigs cannot be restored by testosterone treatment of castrated Meishan pigs (Kojima, Sekimoto, & Degawa, 2010; Kojima & Degawa, 2013).

Overall, these studies suggest that the irreversible imprinting effects
of neonatal testosterone treatment may play a dominant role in the

programming interaction between AhR and the AR receptor because it
is not supervised by the serotonergic system. In turn, up-regulation of
AhR target genes, particularly UGT1A gene expression is an unexplored
mechanism of serotonin deactivation. UDP-glucuronosyltransferase iso-
forms (UGTs) are important in the detoxification of 5- hydroxytrypta-
mine via conjugation to glucuronic acid (King, Rios, Assouline, &
Tephly, 1999). Thus, it seems that a decrease in the level of testosterone
during a brief period of neonatal androgen exposure may block the de-
velopment of autism. Of course, further studies are necessary to confirm
this link.

In fact, a brief period of neonatal androgen exposure is sufficient to
"imprint" or irreversibly program the male rat to express the male-
specific CYP isoforms later on in adult life (Waxman & Chang, 2015).
Castration of male rats at birth eliminates both periods of androgen pro-
duction, and this in turn abolishes the normal adult expression of male
specific CYP3A4 (Einarsson, Gustafsson, & Stenberg, 1973; Waxman &
Chang, 2015).

Dysfunction of the serotonergic system resulting from the reduction
in tryptophan in the diet in the context of liver insufficiency leads to an
increase in testosterone levels in parallel with a decrease in glucocorti-
coids and glucocorticoid receptor (GR) protein levels as well as an in-
crease in STAT6 and ERK1/2 protein levels in the nuclear fraction of
the liver (Kot & Daujat-Chavanieu, 2018). These conditions are associ-
ated with the suppression of CYP3A isoforms at the gene, protein and
activity levels (Kot & Daujat-Chavanieu, 2018). This result is not surpris-
ing because it is known that the GR receptor mediates the hepatic regu-
lation and expression of CYP3A isoforms. On the other hand,
dysfunction of the serotonergic system resulting from the reduction in
tryptophan in the diet in the context of normal liver function is associ-
ated with an increase in CYP3A isoforms at the gene, protein and activity
levels in parallel with a decrease in testosterone level and an increase in
the level of PXR, a confirmed mediator of CYP3A induction (Kot &
Daujat-Chavanieu, 2018). Moreover, physiological and synthetic

<figure><img src="image_4.png" /><figcaption>**Fig. 2.** A. An interplay between testosterone and the serotonergic system in physiological conditions. B. An interplay between testosterone and the serotonergic system in pathophysiological conditions.</figcaption></figure>
## B. An example of pathophysiological conditions

<figure><img src="image_5.png" /><figcaption>**Fig. 2 (continued).**</figcaption></figure>

androgens interact with the GR, and this interaction has significant biological consequences. There is a negative relationship between glucocorticoids and testosterone, and the suppression of testosterone levels by glucocorticoids was observed in rats and humans (Bambino & Hsueh, 1981; Cumming, Quigley, & Yen, 1983). In turn, GR participates in the PXR-mediated induction of CYP3A isoform expression through a unique integrative mechanism (Huss & Kasper, 2000; Pascussi et al., 2008). Notably, PXR activation within the first week of liver transplantation is a prognostic indicator of patient survival (Amer et al., 2019).

Thus, these associations suggest that an efficient interaction between GR and PXR under control of the serotonergic system, which is associated with the upregulation of CYP3A isoforms, is a good prognostic marker of liver regeneration, although it may be disturbed by increased testosterone levels. Worldwide, HCC is more prevalent in men than in women, suggesting that testosterone may be involved in hepatocarcinogenesis (Yu et al., 2000) and that hepatic GR deficiency improved liver steatosis in fatty liver mouse models (Lemke et al., 2008), while CYP3A activity is reduced in individuals with nonalcoholic fatty liver disease (NAFLD), the leading cause of liver disease given its association with obesity, type 2 diabetes, and dyslipidemia (Woolsey, Mansell, Kim, Tirona, & Beaton, 2015).

2.2.1.2. An interplay between testosterone and the serotonergic system during inflammation. Testosterone gonadal depletion and low serum levels of testosterone induce the upregulation of inflammatory cytokines, including IL-1β, nitric oxide synthase (iNOS), tumor necrosis factor (TNF)α, IL-6 and the acute-phase protein C-reactive protein (CRP), leading to BBB dysfunction (Atallah, Mhaouty-Kodja, & Grange-Messent, 2017; Bobjer, Katrinaki, Tsatsanis, Lundberg Giwercman, & Giwercman, 2013). However, supplementation with testosterone is sufficient to restore the impermeability of the BBB (Atallah et al., 2017), and physiological and supraphysiological concentrations of testosterone are sufficient to reduce the expression of TNF-α and IL-1β without affecting IL-6 or CRP expression (Corcoran et al., 2010).

Several studies have focused on tryptophan hydroxylase (TPH)⁻/⁻ knockout mice. In particular, it should be noted that mice with deletion

of Tph1 (TPH1⁻/⁻ knockout mice) gene expression have very low levels of 5-HT in the periphery but maintain normal levels of 5-HT in the brain because the rate production of brain 5-HT by the enzyme TPH2 is directly related to the blood levels of tryptophan and because 5-HT cannot cross the BBB (Walther et al., 2003). In turn, TPH2⁻/⁻ knockout mice exhibit a dramatic reduction in body growth rate and a 60% mortality rate within the first 3 weeks after birth because a lack of brain 5-HT affects postnatal development and may produce long-lasting changes leading to neurodevelopmental disorders (Alenina et al., 2009; Migliarini, Pacini, Pelosi, Lunardi, & Pasqualetti, 2013).

Interestingly, Tph1⁻/⁻ knockout mice exhibit impaired liver regeneration after partial hepatectomy, which, however, is restored after supplementing with the 5-HT precursor 5-HTP (Lesurtel et al., 2006), which effectively increases the synthesis of 5-HT in the brain and periphery. In turn, deletion of the plasma membrane 5-HT transporter, which is engaged in the active removal of 5-HT from the extracellular space, leads to almost completely diminished 5-HT levels in platelets, blood, and liver without impairing liver regeneration and suggests that only very low levels of 5-HT are required for liver regeneration (Matondo et al., 2009).

Therefore, taken together, these observations have raised the question of whether there is an interaction between the peripheral and central serotonergic systems. If so, what are the factors that control this interaction?

Inflammation seems to directly interfere with central and peripheral serotonergic function. It has been shown that the reduction in 5-HT in the gut in TPH1⁻/⁻ mice and the inhibition of 5-HT synthesis with the pharmacologic agent *p*-cholorphenylalanine (PCPA, an irreversible inhibitor of both TPH1 and TPH2) in TPH⁺/⁺ mice not only attenuated the severity of inflammation associated with dextran sulfate sodium (DSS)-induced colitis but also reduced the production of proinflammatory mediators in the gut (Ghia et al., 2009). In turn, subcutaneous administration of the 5-HT precursor, 5-HTP, which easily crosses the BBB and effectively increases the synthesis of 5-HT in the brain (Birdsall, 1998), increases the level of inflammatory markers (including IL-1β) in both TPH1⁻/⁻ mice and TPH⁺/⁺ mice in the context of DSS-
induced colitis, although the increase was higher in TPH1-/- mice than in TPH+/+ mice (Ghia et al., 2009). In another study, TPH1 deficiency intensified neuroinflammation, and the restoration of 5-HT levels by intraperitoneal administration of 5-HTP had no effect on the immunological impact of TPH1 deficiency in a model of autoimmune encephalomyelitis (Nowak et al., 2012). Together, these studies suggest that the effective stimulation of the activity of the TPH1 enzyme is involved in attenuating the inflammatory process induced by the stimulation of the activity of the TPH2 enzyme.

More recent investigations have demonstrated that an altered cytokine profile may be a marker of serotoninergic system dysfunction during liver insufficiency (Kot & Daujat-Chavanieu, 2018). Given that inflammation is associated with tissue regeneration (Eming, Wynn, & Martin, 2017; Karin & Clevers, 2016), it is not surprising to suppose that the regenerative response of the liver can be managed by the inflammatory process under the control of the serotoninergic system. Moreover, there is clear evidence that an altered cytokine profile is associated with changes in the regulation of CYP in the liver under the control of the serotoninergic system and depends on the actual hepatic function (Kot & Daujat-Chavanieu, 2018). It is known that the expression levels and activities of CYP isoforms are downregulated in the liver during the host response to inflammation or infection, leading to alterations in drug clearance and toxin activation (Morgan, 2001). Additionally, the activities of hepatic drug-metabolizing enzymes (CYP) are altered differently during liver regeneration depending on the actual hepatic function (Li et al., 2016). For example, a transient downregulation of the CYP1A2 isoform after hepatectomy was observed, while the expression of CYP3A isoforms remained unaffected (Trautwein, Rakemann, Obermayer-Straub, Niehof, & Manns, 1997). Interestingly, cyclosporine A (CsA), an immunosuppressive drug that is both a substrate and inhibitor of CYP3A (Amundsen, Åsberg, Ohm, & Christensen, 2012), can enhance liver regeneration in a dose-dependent manner (Nagayoshi et al., 2008). Moreover, cyclosporine A (CsA) causes significant decreases in the activity of CYP3A isoforms (Lu, Callahan, & Brunner, 2003). In addition, there is also evidence that cyclosporine A (CsA) may enhance platelet aggregation, and this effect is exclusively mediated by the 5HT2A and 5HT2B receptors (Suehiro et al., 2002). Aggregating platelets release 5-HT (Vanhoutte, 1991), which can stimulate 5-HT serotoninergic receptors. Further studies have integrated the measurements of CYP isoform mRNA and protein levels and activity with measurements of serum 5-HT levels as well as mRNA and protein levels of the 5HT receptors. These studies have demonstrated a key role of the 5HT2A and 5HT2B receptors in the context of liver insufficiency after 5-HT system dysfunction following the consumption of a diet without tryptophan, as well as the suppression of CYP3A isoforms in the context of liver insufficiency, through a mechanism based on posttranscriptional and posttranslational processes involving the repressive IL-4/JAK1/STAT6/SOCS1 mechanism of the JAK2/STAT5b-mediated signal transduction pathway and a mechanism related to the ERK1/2/GR/STAT6 signal transduction pathway (Kot & Daujat-Chavanieu, 2016; Kot & Daujat-Chavanieu, 2018). In turn, in other work, PCPA, — a tryptophan hydroxylase inhibitor that has immunosuppressive properties associated with TPH1 (Ghia et al., 2009) and p-chloroamphetamine (PCA, a specific neurotoxin of the serotoninergic system) caused a selective decrease in the brain 5-HT level in parallel with decreases in the activities and protein levels of CYP3A isoforms (Kot & Daniel, 2011).

### 3. Summary and conclusion

In general, in this review, we presented albumin as a fast-acting peripheral factor that controls the availability of tryptophan and thus plays a key role in controlling the brain and peripheral 5-HT levels and discussed the mechanisms of interactions thyroid hormones and testosterone with albumin. Moreover, we separated positive and negative interactions among the serotoninergic system, immune system, thyroid hormones and testosterone in physiological and pathophysiological

conditions that can supervise the mechanism of the regulation of CYP1A and CYP3A isoforms in the liver and ultimately help to control liver regeneration without stimulating hepatocarcinogenesis.

Based on associations presented in this review, we can conclude the following:

a) Albumin is an endogenous factor that controls the levels of brain and peripheral serotonin.

b) An interference of albumin with thyroid hormones is present both under physiological and pathophysiological conditions.

c) An interference of albumin with testosterone is present both under physiological and pathophysiological conditions.

d) Albumin supervises the mechanism of CYP1A and CYP3A isoform regulation in the liver.

### Declaration of Competing Interest

The authors declare that there are no conflicts of interest.

### Acknowledgement

Research related to this review by the authors are supported in part by grant 2012/07/D/NZ4/00814 (SONATA 4) from the National Science Centre, Poland. This manuscript is supported, in part, by statutory funds to MMRC PAS.

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