GENDER DIFFERENCES IN N-ALKYL PROTOPORPHYRIN-IX PRODUCTION IN RATS AFTER THE ADMINISTRATION OF PORPHYRINOGENIC XENOBIOTICS

Citation
Sgw. Wong et al., GENDER DIFFERENCES IN N-ALKYL PROTOPORPHYRIN-IX PRODUCTION IN RATS AFTER THE ADMINISTRATION OF PORPHYRINOGENIC XENOBIOTICS, Drug metabolism and disposition, 26(8), 1998, pp. 739-744
Citations number
43
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Pharmacy
ISSN journal
0090-9556
Volume
26
Issue
8
Year of publication
1998
Pages
739 - 744
Database
ISI
SICI code
0090-9556(1998)26:8<739:GDINPP>2.0.ZU;2-P
Abstract
The porphyrinogenicity of 3-[(arylthio)ethyl]sydnone (TTMS) and ycarbo nyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine (4-ethylDDC) in rats is d ependent on mechanism-based inactivation of selected isozymes of hepat ic cytochrome P450 (P450), namely P4501A1/2, 2C6, 3A, and 2C11, follow ed 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 inhibit ion of male rat P4503A showed that it was the major source of N-vinylp rotoporphyrin 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, P450 2C11 is also a significant source of N-vinylPP in males. Selective inh ibition of P4503A and 1A1/2 did not decrease N-ethylPP formation in re sponse to 4-ethylDDC administration to male rats, showing that P4503A and 1A1/2 were not sources of N-ethylPP. Thus P4502C6 and 2C11 were th e remaining isozyme candidates to be investigated. When 4-ethylDDC was administered to female rats, N-ethylPP formation was 22% of that prod uced by males. Because female rat livers contain P4502C6 but lack the male specific P4502C11, the likely origin of N-ethylPP in females is P 4502C6. Because males produced markedly more N-ethylPP than females, a nd males have P4502C11 in addition to P4502C6, we conclude that P4502C 11 is the major source of N-ethylPP in males, whereas P4502C6 may also be a significant contributor.