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.
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.
McNamee
J P
JP
Department of Pharmacology and Toxicology, Faculty of Medicine, Queen's University, Kingston, Ontario, Canada.
Marks
G S
GS
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009249:NADP / Q000494:pharmacology; D011524:Protoporphyrins / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013558:Sydnones / Q000008:administration & dosage / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; C102900:N-vinylprotoporphyrin; D011524:Protoporphyrins; D013558:Sydnones; D009249:NADP; C048192:3-(2-(2,4,6-trimethylphenyl)thioethyl)-4-methylsydnone; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System