Ecogenetics The Study of Gene Environment Interactions Daniel W Nebert Amy L Roe PhD

6 Drug-Metabolizing Enzymes

Around 1930-1970, DMEs were considered as a "liver detoxification system" responsible for breaking down drugs and other hydrophobic environmental chemicals for excretion. It is now clear that (1) at least some of these DMEs are located in every eukaryotic cell, (2) almost all DMEs have endogenous compounds as their natural substrates, and (3) many of these DMEs have existed in evolution prior to the divergence of bacteria from eukaryotes, indicating that these DMEs have been responsible for critical life functions long before animal-plant divergence (8, 9).

Since the late 1940s, it has been taught that drug and carcinogen metabolism is carried out by phase I (functionalization) and phase II (conjugation) reactions (Fig. 7.5). Originally, these two coupled reactions were regarded simply as a "liver detoxification system." In the 1960s, some of these activities were then discovered in nonhepatic tissues such as lung, kidney, and gastrointestinal tract—indicating that the activities were not confined only to liver. Then, by the late 1960s, it was realized that some inert chemicals can actually be activated, or metabolically potentiated, to the toxic or carcinogenic intermediate (10). Phase I DMEs, many of which are in the cytochrome P450 superfamily, introduce a functional group, usually a hydroxyl, into their endogenous and exogenous substrates. Thus, a procarcinogen such as benzo[a]pyrene, found in cigarette smoke, becomes metabolically activated to reactive intermediates such as benzo[a]pyrene 7,8-oxide and 4,5-oxide. There are >1000 other polycyclic aromatic hydrocarbons in cigarette smoke. Phase II DMEs—such as glutathione transferases, UDP glucuronosyltransferases and #-acetyltransferases—take the P450-mediated oxygenated product (or any other endogenous or exogenous compound already having functional groups) and use the functional group for conjugation with such moieties as glutathione, glucuronic acid, sulfate, cysteine, or acetate—yielding a very hydrophilic product that can easily be excreted. Table 7.2 lists many of the prototypic phase I and phase II enzymes.

Figure 7.5. Diagram of the fate of drugs (R) entering the cell. The fate of other environmental chemicals is essentially the same. Chemicals can enter the cell by either passive diffusion or active transporters. Either the parent nonmetabolized drug or metabolite reaches its clinical target (efficacy), or the foreign chemical or metabolite can cause toxicity via perturbation of the cell cycle or covalent binding. Reception mechanisms are able to detect the environmental chemical as a "signal" and sometimes can up- or down-regulate phase I and phase II DMEs (9). Transporter proteins can also assist in moving the parent foreign chemical and metabolites out of the cell. Reproduced with permission from Nebert et al. (4).

Figure 7.5. Diagram of the fate of drugs (R) entering the cell. The fate of other environmental chemicals is essentially the same. Chemicals can enter the cell by either passive diffusion or active transporters. Either the parent nonmetabolized drug or metabolite reaches its clinical target (efficacy), or the foreign chemical or metabolite can cause toxicity via perturbation of the cell cycle or covalent binding. Reception mechanisms are able to detect the environmental chemical as a "signal" and sometimes can up- or down-regulate phase I and phase II DMEs (9). Transporter proteins can also assist in moving the parent foreign chemical and metabolites out of the cell. Reproduced with permission from Nebert et al. (4).

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