Xenobiotic metabolizing enzymes interactions

Microbial Transformations and Interactions with the Xenobiotic Metabolizing Enzyme (XME) System... 

Figure 3 Some interactions between gastrointestinal bacteria and the xenobiotic metabolizing enzyme system of the host. Solid lines, host XME system reactions dotted lines, classes of reactions mediated by gastrointestinal bacteria. Specific examples of reaction classes 1-5 are cited in the text. (Modified from Rowland and Tanaka " )...

Because exogenous chemicals can be inducers and/or inhibitors of the xenobiotic-metabolizing enzymes of which they are substrates such chemicals may interact to bring about toxic sequelae different from those that might be expected from any of them administered alone. 

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. 

Although examples are known in which synergistic interactions take place at the receptor site, the majority of such interactions appear to involve the inhibition of xenobiotic-metabolizing enzymes. Two examples involve the insecticide synergists, particularly the methylenedioxyphenyl synergists, and the potentiation of the insecticide malathion by a large number of other organophosphate compounds. 

Humans are exposed continuously and unavoidably to a myriad of potentially toxic chemicals that are inherently lipophilic and, consequently, very difficult to excrete. To effect their elimination, the human body has developed appropriate enzyme systems that can transform metabolically these chemicals to hydrophilic, readily excretable, metabolites. This biotransformation process occurs in two distinct phases. Phase I and Phase II, and involves several enzyme systems, the most important being the cytochromes P450. The expression of these enzyme systems is regulated genetically but can be modulated also other factors, such as exposure to chemicals that can either increase or impair activity. Paradoxically, the same xenobiotic-metabolizing enzyme systems also can convert biologically inactive chemicals to highly reactive intermediates that interact with vital cellular macromolecules and elicit various forms of toxicity. Thus, xenobiotic metabolism does not always lead to deactivation but can result also in metabolic activation with deleterious consequences. 

Our objective in writing this chapter was to present structured data, namely, a reasoned classification of metabolic reactions and their enzymes. In this way, the vast diversity of metabolic reactions and of xenobiotic-metabolizing enzymes ceases to be a vague notion (a heap of stones) and can begin to be grasped as a structured whole made of many interacting parts. 

Barbier, O., Fontaine, C., Fruchart, J. C., and Staels, B. (2004) Genomic and non-genomic interactions of PPARalpha with xenobiotic-metabolizing enzymes. Trends Endocrinol. Metab. 15, 324-330. 

This phytochemical has been found to interact with microsomal xenobiotic-metabolizing enzymes in rodents. Capsaicin has been proposed to inactivate cytochrome P-450 HEl by irreversibly binding to the active sites of the enzyme [135]. Besides cytochrome P-450 HEl, other isoforms of the P-450 super family are also reported to be inhibited by capsaicin. The inhibition by capsaicin of microsomal monooxygenases involved in carcinogen activation implies its chemopreventive potential. 

Uncompetitive inhibition has seldom been reported in studies of xenobiotic metabolism. It occurs when an inhibitor interacts with an enzyme-substrate complex but cannot interact with free enzyme. Both Km and Vmax change by the same ratio, giving rise to a family of parallel lines in a Lineweaver-Burke plot. 

Key Words environmental regulation of xenobiotic metabolism, microsomal enzyme induction, activation of microsomal enzymes, drug-drug interactions, diet-drug interactions... 

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