Metabolic capability, enzyme inducers

Chaturvedi (1993) also examined the effect of mixtures of 10 pesticides (alachlor, aldrin, atrazine, 2,4-D, DDT, dieldrin, endosulfan, lindane, parathion, and toxaphene) administered by oral intubations or by drinking water on the xenobiotic-metabolizing enzymes in male mice. He concluded, The pesticide mixtures have the capability to induce the xenobiotic-metabolizing enzymes, which possibly would not have been observed with individual pesticides at the doses and experimental conditions used in the study. ... 

Environmental chemicals and pollutants are also capable of inducing P450 enzymes. As previously noted, exposure to benzo[a]pyrene and other polycyclic aromatic hydrocarbons, which are present in tobacco smoke, charcoal-broiled meat, and other organic pyrolysis products, is known to induce CYP1A enzymes and to alter the rates of drug metabolism. Other environmental chemicals known to induce specific P450s include the polychlorinated biphenyls (PCBs), which were once used widely in industry as insulating materials and plasticizers, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin, TCDD), a trace byproduct of the chemical synthesis of the defoliant 2,4,5-T (see Chapter 56). 

Diet. The constituents and amount of food (deficiency/starvation) may influence disposition and hence toxicity of chemicals. Food constituents may be enzyme inducers or inhibitors. Lack of food or specific constituents (e.g., protein or vitamins) may decrease metabolic capability, for example, a protein-deficient diet decreases cytochrome P-450 activity. Lack of sulfur amino acids decreases glutathione level. The effect on toxicity will depend on the role of metabolism. 

A number of chemicals with demonstrable suppression of immune function produce this action via indirect effects. By and large, the approach that has been most frequently used to support an indirect mechanism of action is to show immune suppression after in vivo exposure but no immune suppression after in vitro exposure to relevant concentrations. One of the most often cited mechanisms for an indirect action is centered around the limited metabolic capabilities of immunocompetent cells and tissues. A number of chemicals have caused immune suppression when administered to animals but were essentially devoid of any potency when added directly to suspensions of lymphocytes and macrophages. Many of these chemicals are capable of being metabolized to reactive metabolites, including dime-thylnitrosamine, aflatoxin Bi, and carbon tetrachloride. Interestingly, a similar profile of activity (i.e., suppression after in vivo exposure but no activity after in vitro exposure) has been demonstrated with the potent immunosuppressive drug cyclophosphamide. With the exception of the PAHs, few chemicals have been demonstrated to be metabolized when added directly to immunocompetent cells in culture. A primary role for a reactive intermediate in the immune suppression by dimethylnitrosamine, aflatoxin Bi, carbon tetrachloride, and cyclophosphamide has been confirmed in studies in which these xenobiotics were incubated with suspensions of immunocompetent cells in the presence of metabolic activation systems (MASs). Examples of MASs include primary hepatocytes, liver microsomes, and liver homogenates. In most cases, confirmation of a primary role for a reactive metabolite has been provided by in vivo studies in which the metabolic capability was either enhanced or suppressed by the administration of an enzyme inducer or a metabolic inhibitor, respectively. 

Experiments have used cells with a metabolic capability that may plausibly be predicted as relevant to that of the xenobiotic. For example, elective enrichment failed to yield organisms able to grow at the expense of dibenzo-[l,4]-dioxin, but its metabolism could be studied in a strain of Pseudomonas sp. capable of growth with naphthalene (Klecka and Gibson 1979). Cells were grown with salicylate (1 g/1) in the presence of dibenzo-[l,4]-dioxin (0.5 g/1), and two metabolites of the latter were isolated a s-l,2-dihydro-l,2-diol and 2-hydroxydibenzo-l,4-dioxin. The former is consistent with the established dioxygenation of naphthalene and the role of salicylate as coordinate inducer of the relevant enzymes for conversion of naphthalene into salicylate. 

The pattern of induction of metabolizing and of conjugating enzymes may be quite different, even though, for example, cytochrome P-450 inducers are capable of inducing both glutathione transferase and UDP glucuronosyl transferase activities (Andersson et al. 1985). 

Clearly, no one animal model or combination of animal models reflects the metabolic capabilities of humans. By having a complete understanding of the factors (e.g., inducers, inhibitors, and effect of disease state) that alter the expression and activity of the enzyme responsible for the metabolism of a particular compound, and by a determination of responsible isoforms and patient phenotyping, it may be possible to predict drug interactions and metabolic clearance. 

Salmonella typhimurium. Although most nitro PAHs are direct-acting mutagens in Salmonella typhimurium, these compounds must be metabolized to bind covalently to DNA (71,92,112). S. typhimurium contains a family of nitroreductases which are capable of reducing nitro PAHs, and strains which are deficient in these enzymes generally show decreased sensitivity toward nitro PAH-induced mutations (27,92,113-114). These observations suggest that reduced metabolic intermediates may be the critical reactive electrophiles. 

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