Microsomal monooxygenase systems contain multiple isozymes of cytochrome P-450 which contribute differentially to the oxidative metabolism of endogenous and exogenous substrates; isozyme differences in Km, Vmax, regioselectivity and stereoselectivity are common. Hence, modulation of the relative amounts of various P-450 isozymes can have pronouced effects on metabolism of endogenous and exogenous chemicals. For this reason we are studying isozyme selectivity and tissue/cell selectivity of suicide inhibitors of cytochrome P-450. The suicide inhibition by l-aminobenzotriazole (ABT) and some of its novel N-alkylated derivatives, which we synthesized and characterized, is being studied in rabbit lung and liver. Although ABT is a potent suicide inhibitor, it shows little P-450 isozyme selectivity. N-Alpha-methylbenzyl-ABT, on the other hand, is much more potent and highly selective. At certain doses in vivo it destroys only isozyme 2-catalyzed benzphetamine N-demethylase activity in lung, having no effect on isozymes 5 and 6 in lung and no effect on any of the parameters tested in liver.
