Cytochrome P4503A is the major source of N-vinylprotoporphyrin IX formation after administration of 3-[2- (2,4,6-trimethylphenyl) thioethyl]-4-methylsydnone to untreated and dexamethasone-pretreated rats
McNamee, J.P.; Marks, G.S.
Drug Metabolism and Disposition the Biological Fate of Chemicals 24(8): 872-878
1996
ISSN/ISBN: 0090-9556 PMID: 8869822 Document Number: 456415
The sydnone, 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone (TTMS), which has previously been shown to cause mechanism-based inactivation of rat hepatic cytochrome P450 (P450) 1A and 3A, was shown to cause in vitro mechanism-based inactivation of rat P450s 2B1, 2C6, and 2C11, but not of P4502A1/2. Administration of TTMS to rats is known to cause degradation of rat hepatic P450 by heme N-alkylation yielding N-vinylprotoporphyrin IX (N-vinylPP). Pretreatment of rats with beta-naphthoflavone (beta NF) failed to increase hepatic N-vinylPP after TTMS administration. Because beta NF causes a marked increase in hepatic levels of P4501A, we conclude that P4501A of rat liver is not a quantitatively important source of N-vinylPP from TTMS. The increased formation of N-vinylPP in phenobarbital (PB)- and dexamethasone (DEX)-pretreated rats suggested that an inducible P450 isozyme (e.g. P4502B1/2, P4503A, or both) is/are an important contributor to N-vinylPP formation from TTMS. When troleandomycin (TAO) (a selective inhibitor of P4503A) was coadministered with TTMS, N-vinylPP formation was reduced to 25% of control in DEX-pretreated rats and to 34% of control in untreated (UT) rats, showing that P4503A was quantitatively the major source of N-vinylPP formation in UT- and DEX-pretreated rats. No significant differences were found in the formation of the ring A-substituted (NA), ring B-substituted (NB), ring C-substituted (NC), and ring D-substituted (ND) regioisomers of N-vinylPP among UT, beta NF-, PB-, or DEX-pretreated rats. Regioisomer data, in addition to data obtained with TAO, indicate that a single inducible form of P450, namely P4503A, is responsible for the bulk of N-vinylPP formation in UT and DEX-pretreated rat liver after TTMS administration.