Xenobiotic metabolism phase

ISOFORMS OF CYTOCHROME P450 HYDROXYLATE A MYRIAD OF XENOBIOTICS IN PHASE 1 OF THEIR METABOLISM... 

Researchers focused on the metabolically competent human hepatoma cell line HepG2 as a model of human liver. HepG2 cells are a well-known hepatoma cell line that retains many of the morphological characteristics of liver parenchymal cells. This model is often used as a useful tool for HRA/ERA-oriented chemical risk assessment due to the expression of antioxidant and xenobiotic metabolizing enzymes (in particular phase I and phase II enzymes responsible for the bioactivation/detoxification of various xenobiotics) that can be induced or inhibited by dietary and non-dietary agents [28-30]. 

Egaas, E., J.U. Skaare, N.O. Svendsen, M. Sandvik, J.G. Falls, W.C. Dautennan, T.K. Collier, and J. Netland. 1993. A comparative study of effects of atrazine on xenobiotic metabolizing enzymes in fish and insect, and of the in vitro phase II atrazine metabolism in some fish, insects, mammals and one plant species. Comp. Biochem. Physiol. 106C 141-149. 

Reflecting the increasing importance of drug transporters in pharmacokinetics, we need to extend the historical two-phase concept for the metabolism of xenobiotics. As shown in Figure 15.1, the metabolic phases I (oxidation) and II (conjugation) are flanked by drug transporter phases 0 (uptake) and III (export). Phase 0 is the first step... 

The ability of PBBs to induce hepatic Phase I xenobiotic metabolizing enzymes (cytochrome P-450-dependent monooxygenases) is well documented (Dannan et al. 1978b, 1982a, 1982b, 1983 Ecobichon et al. 1979 Moore et al. 1978, 1979 Parkinson et al. 1983 Robertson et al. 1982 Schramm et al. 1985). PBB mixtures were classified as "mixed-type" inducers of hepatic microsomal monooxygenases and... 

The field of xenobiotic metabolism is rich with a myriad of different, often competing, pathways of metabolism. Efforts at cDNA expression have only begun to develop comprehensive systems for the analysis of all Phase I and all Phase II enzymes. A comprehensive set of human cytochrome P450 and Phase II enzymes is not available in the context of a single host cell type, but given the rate of progress, we can look forward to nearly complete systems in the near future. 

During the course of metabolism, and particularly during phase I reactions, reactive intermediates that are much more toxic than the parent compound may be produced. Thus xenobiotic metabolism may be either a detoxication or an activation process. 

Biotransformation refers to changes in xenobiotic compounds as a result of enzyme action. Reactions not mediated by enzymes may also be important. As examples of nonenzymatic transformations, some xenobiotic compounds bond with endogenous biochemical species without an enzyme catalyst, undergo hydrolysis in body fluid media, or undergo oxidation-reduction processes. However, the metabolic phase I and phase II reactions of xenobiotics discussed here are enzymatic. 

Mehrotra K, Morgenstem R, Ahlberg MB, et al. 1999. Hypophysectomy and/or peroxisome proliferators strongly influence the levels of phase II xenobiotic metabolizing enzymes in rat testis. Chem Biol Interact 122 73-87. 

Examples of oxidative reactions are shown in Table 3.3. Generally, reduction and hydrolysis reactions play subordinate roles in xenobiotic metabolism compared to oxidation reactions. Examples of reduction and hydrolysis reactions are shown in Tables 3.4 and 3.5, respectively. To reiterate the net result of phase I reactions is the... 

TABLE 10.1. Phase I Xenobiotic-Metabolizing Enzymes with Examples of Substrates... 

Figure 13.14. Xenobiotic metabolism and roles of phase II genes.

Xenobiotics are biotransformed by phase I enzymes and phase II conjugation reactions to form a variety of metabolites that are generally more water-soluble and less toxic than the parent compound. Occasionally, the enzymic action of phase I or II systems leads to the formation of unstable intermediates or reactive metabolites that are toxic or carcinogenic. Many physiological factors influence the rate of xenobiotic metabolism and the relative importance of different pathways of metabolic activation or detoxication. 

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