Vol. 26, Issue 8, 739-744, August 1998

Gender Differences in N-Alkyl Protoporphyrin IX Production in Rats after the Administration of Porphyrinogenic Xenobiotics

Simon G.W. Wong, Susan M. Kobus, James P. McNamee, and Gerald S. Marks

Department of Pharmacology and Toxicology, Faculty of Medicine, Queen's University

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.