Cytochrome P450 system isoforms

The widespread use of isoniazid prophylaxis for tuberculosis has focused attention on the liver injury caused by this drug. About 20% of patients treated with isoniazid will show elevated blood concentrations of liver enzymes and bilirubin that subside as treatment is continued (25). However/ clinical hepatitis develops in some patientS/ and these reactions can prove fatal. Current understanding of the mechanism of isoniazid-induced hepatotoxicity is based on the metabolic pathways shown in Figure 16.6 (26/ 27). It has been demonstrated in an animal model that hepatotoxicity is correlated with plasma concentrations of hydrazine but not of acetylhydrazine or isoniazid (28)/ and that pretreatment with an amidase inhibitor can prevent toxicity (27). However/ it is postulated that hydrazine is further metabolized to a chemically reactive he pa to toxin by the cytochrome P450 system/ and in vitro studies with hepatocytes have implicated CYP2E1 as the cytochrome P450 isoform responsible for cytotoxic metabolite formation (29). 

Kobayashi, K., K. Urashima, N. Shimada, and K. Chiba (2002). Substrate specificity for rat cytochrome P450 (CYP) isoforms Screening with cDNA-expressed systems of the rat. Biochem. Pharmacol. 63, 889-896. 

Drug interactions involving AEDs are shown in Table 52-5. Phenobarbital, phoiytom, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP450), epoxide hydrolase, and uridine diphosphate gjucuronosyltransferase enzyme systems. Valproic acid inhibits many hepatic enzjrme systems and displaces some drugs from plasma albumin. Felbamate and topiramate can act as inducers with some isoforms and inhibitors with others. 

K. Chiba (2003). Selectivities of human cytochrome P450 inhibitors toward rat P450 isoforms Study with cDNA-expressed systems of the rat. Drug Metab. Dispos. 31, 833-836. 

The successful solution of the many bacterial cytochrome crystal structures was largely due to the simple fact that they are soluble. Mammalian microsomal P450s, on the other hand, are membrane bound and hence insoluble. The A -terminal region of the microsomal isoforms is believed to form a single membrane-spanning a-helix that tethers it close to the other protein in the system, the NADP/H dependent cytochrome reductase. This reductase is the source of electrons for the catalytic mechanism described earlier. 

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