Cytochrome CYP sources of N-alkylprotoporphyrin IX after administration of porphyrinogenic xenobiotics to rats.

Cytochrome P-450 (CYP) 3A2 and CYP2C11 are sources of 70 and 30%, respectively, of N- vinylprotoporphyrin IX ( N -vinylPP) formation after administration of 3-[(arylthio)ethyl]sydnone (TTMS) to rats. Female rats receiving TTMS were pretreated with dexamethasone, which induces CYP3A1 preferentially to CYP3A2. The resulting 12-fold increase in N- vinylPP formation showed that CYP3A1 was also a source of N- vinylPP. Phenobarbital (PB) pretreatment, which induces CYP2B1/2 and 3A1/2 in male rats, increased N- vinylPP formation after TTMS administration. Troleandomycin, a selective CYP3A inhibitor, was unable to decrease TTMS-mediated N- vinylPP formation in PB-treated male rats, indicating that CYP2B1/2 were sources of N- vinylPP. This conclusion was supported by demonstrating a 15-fold increase in TTMSinduced N- vinylPP formation in female rats after CYP2B1/2 induction with PB pretreatment. Allylispropylacetamide (AIA) inactivates rat CYP2B1/2, 2C6, 2C7, 2C11, and 3A1/2. Troleandomycin was unable to decrease N- AIA protoporphyrin IX adduct ( N -AIAPP) formation, showing that CYP3A1/2 were not susceptible to AIA-mediated N- alkylation. N- AIAPP formation in females was approximately 30% of that in males, and thus we attribute 30% of N- AIAPP formation in males to the non-gender-specific isozymes (CYP2C6, 2C7, and/or 2B1/2), whereas approximately 70% originates from CYP2C11. PB treatment in female rats resulted in a 5-fold increase in N- AIAPP formation, showing that CYP2B1/2 were also susceptible to N- alkylation mediated by AIA. 1-Aminobenzotriazole elicited formation of equivalent amounts of N ′ N -aryl bridged protoporphyrin IX in male and female rat liver, demonstrating that nonselective mechanism-based inactivation is accompanied by nonselective conversion of the CYP heme moieties to N ′ N -aryl bridged protoporphyrin IX.