It is noteworthy that CYP3A4 alone is responsible for the metabolism of over 50% of the prescription drugs metabolized by the liver. The involvement of individual P450s in the metabolism of a given drug may be screened in vitro by means of selective functional markers, selective chemical P450 inhibitors, and P450 antibodies. In vivo, such screening may be accomplished by means of relatively selective noninvasive markers, which include breath tests or urinary analyses of specific metabolites after administration of a P450-selective substrate probe.
Some of the chemically dissimilar P450 substrate drugs, on repeated administration, induce P450 expression by enhancing the rate of its synthesis or reducing its rate of degradation (Table 4–2). Induction results in accelerated substrate metabolism and usually in a decrease in the pharmacologic action of the inducer and also of co-administered drugs. However, in the case of drugs metabolically transformed to reactive metabolites, enzyme induction may exacerbate metabolite-mediated toxicity.
Various substrates induce P450 isoforms having different molecular masses and exhibiting different substrate specificities and immunochemical and spectral characteristics.
Environmental chemicals and pollutants are also capable of inducing P450 enzymes. 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-pdioxin (dioxin, TCDD), a trace byproduct of the chemical synthesis of the defoliant 2,4,5-T (see Chapter 56).