CYTOCHROME P4503A IS THE MAJOR SOURCE OF N-VINYLPROTOPORPHYRIN-IX FORMATION AFTER ADMINISTRATION OF 2-(2,4,6-TRIMETHYLPHENYL)THIOETHY]-4-METHYLSYDNONE TO UNTREATED AND DEXAMETHASONE-PRETREATED RATS
Jp. Mcnamee et Gs. Marks, CYTOCHROME P4503A IS THE MAJOR SOURCE OF N-VINYLPROTOPORPHYRIN-IX FORMATION AFTER ADMINISTRATION OF 2-(2,4,6-TRIMETHYLPHENYL)THIOETHY]-4-METHYLSYDNONE TO UNTREATED AND DEXAMETHASONE-PRETREATED RATS, Drug metabolism and disposition, 24(8), 1996, pp. 872-878
The sydnone, -(2,4,6-trimethyIphenyl)thioethyl]-4-methylsydnone (TTMS)
, which has previously been shown to cause mechanism-based inactivatio
n 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 caus
e degradation of rat hepatic P450 by heme N-alkylation yielding N-viny
lprotoporphyrin IX (N-vinylPP), Pretreatment of rats with beta-naphtho
flavone (beta NF) failed to increase hepatic N-vinylPP after TTMS admi
nistration. Because beta NF causes a marked increase in hepatic levels
of P4501A, we conclude that P4501A of rat liver is not a quantitative
ly important source of N-vinylPP from TTMS. The increased formation of
N-vinylPP in phenobarbital (PB)- and dexamethasone (DEX)-pretreated r
ats suggested that an inducible P450 isozyme (e.g. P4502B1/2, P4503A,
or both) is/are an important contributor to N-vinylPP formation from T
TMS. When troleandomycin (TAO) (a selective inhibitor of P4503A) was c
oadministered with TTMS, N-vinylPP formation was reduced to 25% of con
trol in DEX-pretreated rats and Po 34% of control in untreated (UT) ra
ts, showing that P4503A was quantitatively the major source of N-vinyl
PP formation in UT- and DEX-pretreated rats. No significant difference
s were found in the formation of the ring A-substituted (N-A), ring B-
substituted (N-B), ring C-substituted (N-C), and ring D-substituted (N
-D) regioisomers of N-vinylPP among UT, beta NF-, PB-, or DEX-pretreat
ed rats, Regioisomer data, in addition to data obtained with TAO, indi
cate that a single inducible form of P450, namely P4503A, is responsib
le for the bulk of N-vinylPP formation in UT and DEX-pretreated rat li
ver after TTMS administration.