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
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.