Comparitive study of hepatic coumarin hydroxylase [cyp2a-5] induction by heavy metal tin

ABSTRACT

The selective induction of the hepatic coumarin hydroxylase [Cyp 2a-5] elicited by the heavy metal tin [Sn C12] has been compared in male NMRI mice with that of the standard inducers, phenobarbitone [PB] and 3-methylcholanthrene [MC]. Although the standard inducers, PB and MC increase the microsomal specific content of cytochrome P 450 [P 450/mg microsomal protein], stannous chloride leads to a decrease in this concentration. On the other hand, regarding Cyp 2a-5 activity, ethoxycoumarin O-deethylase was increased to about 3.5-fold and coumarin 7-hydroxylase as much as 8-fold after pretreatment with stannous chloride. This-increase was much higher than that caused by PB, the only well known inducer of coumarin 7-hydroxylase and MC. However, the 2.2- or 2.4-fold increase in the N-demethylation of ehtylmorphine of benzphetamine, the model substrate used to visualize the latent PB-induction, by PB were insignificantly decreased after pretreatment by stannous chloride. The same is true when ethoxyresorufin O-deethylation, which would indicate MC-induction type was considered. Stannous chloride did not affect such activity whereas the MC increases it to about 11-fold. The data indicate that the heavy metal salt-stannous chloride causes induction of microsomal monooxygenase complex selective for coumarin 7-hydroxylase and 7-ethoxycoumarin O-deethylase and does not affect the rate of metabolism of model substrates, which would indicate a PB-or MC-type of induction