Differential stereoselectivity on metabolism of triphenylene by cytochromes P-450 in liver microsomes from 3-methylcholanthrene and phenobarbital-treated rats

Journal Article · Tue Jan 05 04:00:00 EST 1988 · J. Biol. Chem.; (United States)

OSTI ID:6922179

Thakker, D R; Boehlert, C; Mirsadeghi, S; Levin, W; Ryan, D E; Thomas, P E; Yagi, H; Pannell, L K; Sayer, J M; Jerina, D M

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 /sup 18/O-enriched water showed that attack of water was exclusively at the allylic 2-position of the arene oxide, indicating that the 2R,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 (>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 approx. 20 s under the incubation conditions. This study may represent the first attempt to address stereochemical consequences of a rapidly racemizing intermediary metabolite.

• Research Organization: Food and Drug Administration, Bethesda, MD (USA)
• OSTI ID: 6922179
• Journal Information: J. Biol. Chem.; (United States), Journal Name: J. Biol. Chem.; (United States) Vol. 263:1; ISSN JBCHA
• Country of Publication: United States
• Language: English

Related Subjects

3-METHYLCHOLANTHRENE
560300* -- Chemicals Metabolism & Toxicology
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANESTHETICS
ANIMALS
ANTICONVULSANTS
AROMATICS
AZINES
BARBITURATES
BIOLOGICAL EFFECTS
BODY
CARCINOGENESIS
CELL CONSTITUENTS
CENTRAL NERVOUS SYSTEM DEPRESSANTS
CONDENSED AROMATICS
DIGESTIVE SYSTEM
DRUGS
ENZYMES
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROCARBONS
HYDROLASES
HYPNOTICS AND SEDATIVES
LIVER
MAMMALS
METABOLISM
MICROSOMES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANOIDS
ORGANS
PATHOGENESIS
PHENOBARBITAL
POLYCYCLIC AROMATIC HYDROCARBONS
PYRIMIDINES
RACEMIZATION
RATS
RODENTS
TRIPHENYLENE
VERTEBRATES