<i>In vitro</i> hepatic metabolism of the natural product quebecol
Creators: name: Bernardes, Gabriel
name: Krol, Ed S.
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biophysics
subject: Biochemistry
subject: Molecular Biology
subject: Physiology
subject: FOS: Biological sciences
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: Ecology
subject: Developmental Biology
subject: Cancer

description: Quebecol (2,3,3-tri-(3-methoxy-4-hydroxyphenyl)-1-propanol) is a polyphenolic compound, which is formed during maple syrup production from <i>Acer</i> spp. Quebecol bears structural similarities to the chemotherapy drug tamoxifen, which has led to synthesis of structural analogues and investigations into their pharmacological properties, however there are no reports on the hepatic metabolism of quebecol.This interest in therapeutic properties spurred us to investigate the <i>in vitro</i> microsomal Phase I and II metabolism of quebecol. We were unable to detect any P450 metabolites for quebecol in either human liver microsomes (HLM) or rat liver microsomes (RLM). In contrast we observed marked formation of three glucuronide metabolites in both RLM and HLM, suggesting that clearance <i>via</i> Phase II pathways is likely to predominate.To further understand the hepatic contribution to first-pass glucuronidation we have validated an HPLC method following FDA and EMA guidelines (selectivity, linearity, accuracy, and precision) to quantify quebecol in microsomes. <i>In vitro</i> enzyme kinetics were performed for quebecol glucuronidation by HLM including 8 concentrations from 5–30 µM. We determined a Michaelis-Menten constant (K<sub>M</sub>) of 5.1 µM, intrinsic clearance (Cl<sub>int,u</sub>) of 0.038 ± 0.001 mL/min/mg, and maximum velocity (V<sub>max</sub>) of 0.22 ± 0.01 µmol/min/mg. Quebecol (2,3,3-tri-(3-methoxy-4-hydroxyphenyl)-1-propanol) is a polyphenolic compound, which is formed during maple syrup production from <i>Acer</i> spp. Quebecol bears structural similarities to the chemotherapy drug tamoxifen, which has led to synthesis of structural analogues and investigations into their pharmacological properties, however there are no reports on the hepatic metabolism of quebecol. This interest in therapeutic properties spurred us to investigate the <i>in vitro</i> microsomal Phase I and II metabolism of quebecol. We were unable to detect any P450 metabolites for quebecol in either human liver microsomes (HLM) or rat liver microsomes (RLM). In contrast we observed marked formation of three glucuronide metabolites in both RLM and HLM, suggesting that clearance <i>via</i> Phase II pathways is likely to predominate. To further understand the hepatic contribution to first-pass glucuronidation we have validated an HPLC method following FDA and EMA guidelines (selectivity, linearity, accuracy, and precision) to quantify quebecol in microsomes. <i>In vitro</i> enzyme kinetics were performed for quebecol glucuronidation by HLM including 8 concentrations from 5–30 µM. We determined a Michaelis-Menten constant (K<sub>M</sub>) of 5.1 µM, intrinsic clearance (Cl<sub>int,u</sub>) of 0.038 ± 0.001 mL/min/mg, and maximum velocity (V<sub>max</sub>) of 0.22 ± 0.01 µmol/min/mg.