It takes more than one—Is a single UGT polymorphism enough to bother detoxification?
Authors: Christoph G. Dietrich, Andreas Geier
Journal: Hepatology (2005)

To the Editor: Girard et al.1 investigated the influence of UGT1A1 polymorphisms on glucuronidation of the heterocyclic amine PhIP. While this study is technically very well conducted and yields clear results, we have serious concerns regarding the interpretation of the data. The title of the article does not reflect the evidence extracted from the obtained results. Since only one compound (namely, PhIP) and only one enzymatic class (namely, UGT) in one organ (liver) was tested, no general conclusions can be drawn regarding "dietary carcinogen detoxification." It has been established in comparable studies that detoxification of (dietary) carcinogens can vary immensely depending on the specific compound.2, 3 Also problematic is the isolated analysis of microsomal enzyme activity. Metabolism consists of several successive steps that should be studied in toto (Fig. 1). Most important for hepatic glucuronidation capacity is transport out of the hepatocyte, either at the canalicular or the basolateral membrane.4 This function is served by several members of the ABCC family of ABC transporters. We and others have shown that conjugation depends on the integrity of such transport systems.5-7 It is possible to determine the isolated hepatic glucuronidation capacity as done by Girard and coworkers. However, the reported data do not provide any clinical relevant information about in vivo glucuronidation capacity and therefore should be interpreted with caution. Successive steps in metabolism of the heterocyclic amine PhIP in the hepatocyte comprising phases 0 to III. Forming of glucuronidated metabolites critically depends on transport activity of MRP2/ABCC2 at the canalicular or MRP3/ABCC3 and MRP4/ABCC4 at the basolateral membrane. Lack or decrease of UGT1 activity can be circumvented by other phase II enzymes. BCRP, breast cancer resistance protein; CYP, cytochrome P450 isoforms; MRP, multidrug resistance-associated protein; OATP, organic anion transport protein; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; SULT, sulfotransferase. Additionally, we and others have shown in rodents that compensatory sulfation (conferred by cytosolic sulfotransferases) takes place in the hereditary absence of all Ugt1a isoforms.2 Furthermore, the absence of all of these isoforms leads to reduced rather than increased DNA adduct formation in the colon,8 the target organ of carcinogenicitiy of PhIP in rats and, presumably, in humans as well. It is an open question whether other metabolites (4′-OH-PhIP, O-glucuronidated PhIP, or sulfated 4′-OH-PhIP) can form under the condition of the human UGT1A1*28 polymorphism. However, it seems reasonable to assume that such compensatory pathways also exist in humans. Using the methodological approach of Girard and coworkers, it is impossible to identify such compensatory pathways of detoxification; hence, overall detoxification in the human liver cannot be quantified. The authors drew a link between their results and the study from Peters et al.9 We consider this extrapolation invalid for two reasons: It is incorrect to compare urinary excretion of metabolites with the formation of these metabolites in isolated liver microsomes, as urinary excretion of metabolites involves only those metabolites that have been exported via the basolateral but not the canalicular membrane (methodological concern). Additionally, Peters et al. themselves clearly stated the limitations of their findings because the study involved a multitest situation (statistical concern). Therefore, the study of Girard et al. cannot serve as a confirmation of the study of Peters et al., and vice versa. In summary, in our opinion, future studies of dietary carcinogen detoxification should always include the analysis of metabolism in the context of the orchestrated enzymatic environment (phase 0–phase III) as present in the respective compartments before drawing conclusions on overall detoxification. Christoph G. Dietrich*, Andreas Geier*, * Department of Gastroenterology and Hepatology, Aachen University, Aachen, Germany.