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

Cytochrome P-450 (CYP) 3A2 and CYP2C11 are sources of 70 and 30%, respectiv ely, of N-vinylprotoporphyrin IX (N-vinylPP) formation after administration of 3-[(arylthio)ethyl]sydnone (TTMS) to rats. Female rats receiving TTMS w ere pretreated with dexamethasone, which induces CYP3A1 preferentially to C YP3A2. The resulting 12-fold increase in N-vinylPP formation showed that CY P3A1 was also a source of N-vinylPP. Phenobarbital (PB) pretreatment, which induces CYP2B1/2 and 3A1/2 in male rats, increased N-vinylPP formation aft er TTMS administration. Troleandomycin, a selective CYP3A inhibitor, was un able to decrease TTMS-mediated N-vinylPP formation in PB-treated male rats, indicating that CYP2B1/2 were sources of N-vinylPP. This conclusion was su pported by demonstrating a 15-fold increase in TTMS-induced N-vinylPP forma tion in female rats after CYP2B1/2 induction with PB pretreatment. Allylisp ropylacetamide (AIA) inactivates rat CYP2B1/2, 2C6, 2C7, 2C11, and 3A1/2. T roleandomycin was unable to decrease N-AIA protoporphyrin IX adduct (N-AIAP P) formation, showing that CYP3A1/2 were not susceptible to AIA-mediated N- alkylation. N-AIAPP formation in females was approximately 30% of that in m ales, and thus we attribute 30% of N-AIAPP formation in males to the non-ge nder-specific isozymes (CYP2C6, 2C7, and/or 2B1/2), whereas approximately 7 0% originates from CYPPC11. PB treatment in female rats resulted in a 3-fol d increase in N-AIAPP formation, showing that CYP2B1/2 were also susceptibl e to N-alkylation mediated by AIA. 1-Aminobenzotriazole elicited formation of equivalent amounts of N'N-aryl bridged protoporphyrin IX in male and fem ale rat liver, demonstrating that nonselective mechanism-based inactivation is accompanied by nonselective conversion of the CYP hems moieties to N'N- aryl bridged protoporphyrin IX.