Differential stereoselectivity on metabolism of triphenylene by cytochromes P-450 in liver microsomes from 3-methylcholanthrene- and phenobarbital-treated rats.
Metabolism of triphenylene by liver microsomes from control, phenobarbital(PB)-treated rats and 3-methylcholanthrene(MC)-treated rats as well as by a purified system reconstituted with cytochrome P-450c in the absence or presence of purified microsomal epoxide hydrolase was examined. Control microsomes metabolized triphenylene at a rate of 1.2 nmol/nmol of cytochrome P-450/min. Treatment of rats with PB or MC resulted in a 40% reduction and a 3-fold enhancement in the rate of metabolism, respectively. Metabolites consisted of the trans-1,2-dihydrodiol as well as 1-hydroxytriphenylene, and to a lesser extent 2-hydroxytriphenylene. The (-)-1R,2R-enantiomer of the dihydrodiol predominated (70 to 92%) under all incubation conditions. Incubation of racemic triphenylene 1,2-oxide with microsomal epoxide hydrolase produced dihydrodiol which was highly enriched (80%) in the (-)-1R,2R-enantiomer. Experiments with 18O-enriched water showed that attack of water was exclusively at the allylic 2-position of the arene oxide, indicating that the 1R,2S-enantiomer of the oxide was preferentially hydrated by epoxide hydrolase. Thiol trapping experiments indicated that liver microsomes from MC-treated rats produced almost exclusively (greater than 90%) the 1R,2S-enantiomer of triphenylene 1,2-oxide whereas liver microsomes from PB-treated rats formed racemic oxide. The optically active oxide has a half-life for racemization of only approximately 20 s under the incubation conditions. This study may represent the first attempt to address stereochemical consequences of a rapidly racemizing intermediary metabolite.
Thakker
D R
DR
Laboratory of Molecular Pharmacology, Food and Drug Administration, Bethesda, Maryland 20892.
Boehlert
C
C
Mirsadeghi
S
S
Levin
W
W
Ryan
D E
DE
Thomas
P E
PE
Yagi
H
H
Pannell
L K
LK
Sayer
J M
JM
Jerina
D M
DM
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002911:Chrysenes / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010103:Oxygen Isotopes; D010616:Phenanthrenes / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002911:Chrysenes; D010103:Oxygen Isotopes; D010616:Phenanthrenes; C009590:triphenylene; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D004851:Epoxide Hydrolases; D010634:Phenobarbital