It takes more than one—Is a single UGT polymorphism enough to bother detoxification?
✍ Scribed by Christoph G. Dietrich; Andreas Geier
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- English
- Weight
- 60 KB
- Volume
- 42
- Category
- Article
- ISSN
- 0270-9139
No coin nor oath required. For personal study only.
✦ Synopsis
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][6][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.
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 (4Ј-OH-PhIP, O-glucuronidated PhIP, or sulfated 4Ј-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.