Gender differences in N-alkyl protoporphyrin IX production in rats after the administration of porphyrinogenic xenobiotics.

Abstract

The porphyrinogenicity of 3-[(arylthio)ethyl]sydnone (TTMS) and 3, 5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine (4-ethylDDC) in rats is dependent on mechanism-based inactivation of selected isozymes of hepatic cytochrome P450 (P450), namely P4501A1/2, 2C6, 3A, and 2C11, followed by formation of ferrochelatase-inhibitory N-alkyl protoporphyrin IX (N-alkylPP). The objective of this study was to determine which P450 isozymes were sources of the N-alkylPPs. Previously, selective inhibition of male rat P4503A showed that it was the major source of N-vinylprotoporphyrin IX after TTMS administration. In the present study, when TTMS was administered to female rats, which lack P4503A2 and 2C11, N-vinylPP formation was 2.3% of that produced by males, which have both of these isozymes. Therefore, although P4503A2 is a major source, P4502C11 is also a significant source of N-vinylPP in males. Selective inhibition of P4503A and 1A1/2 did not decrease N-ethylPP formation in response to 4-ethylDDC administration to male rats, showing that P4503A and 1A1/2 were not sources of N-ethylPP. Thus P4502C6 and 2C11 were the remaining isozyme candidates to be investigated. When 4-ethylDDC was administered to female rats, N-ethylPP formation was 22% of that produced by males. Because female rat livers contain P4502C6 but lack the male specific P4502C11, the likely origin of N-ethylPP in females is P4502C6. Because males produced markedly more N-ethylPP than females, and males have P4502C11 in addition to P4502C6, we conclude that P4502C11 is the major source of N-ethylPP in males, whereas P4502C6 may also be a significant contributor.