A comparative study on the contribution of cytochrome P450 isozymes to metabolism of benzene, toluene and trichloroethylene in rat liver.
The contribution of P450IIE1, P450IIC11/6, P450IIB1/2 and P450IA1/2 to the formation of chloral hydrate (CH) from trichloroethylene (TRI) was investigated in microsomes from control, ethanol-, phenobarbital (PB)- and 3-methylcholanthrene (MC)-treated rats using monoclonal antibodies (MAbs) to the respective P450 isozymes, and compared with their roles in benzene and toluene metabolism. Anti-P450IIE1 inhibited the formation of CH from TRI more strongly in microsomes from ethanol-treated rats than in microsomes from control rats at low concentration of TRI when net inhibition was compared. Anti-P450IIC11/6 inhibited CH formation in microsomes from control and PB-treated rats at high, not low, concentration of TRI, but the net inhibition in control microsomes was less than that due to anti-P450IIE1. Anti-P450IIB1/2 and anti-P450IA1/2 also inhibited CH formation from TRI in microsomes from PB- and MC-treated rats, respectively, stronger at high substrate concentration than at low concentration. These results indicate that P450IIE1, P450IIC11/6, P450IIB1/2 and P450IA1/2 are involved in the metabolic step from TRI to CH, and the first isozyme may be a low-Km TRI oxidase and the others high-Km one. Comparing the contributions of four isozymes to benzene, toluene and TRI metabolism, all four acted in the metabolism of these compounds, but P450IIE1 did not catalyse o-cresol formation nor P450IA1/2 benzyl alcohol formation from toluene, suggesting regioselectivity of toluene metabolism in the action of these two isozymes. The contribution of P450IIE1 in benzene and TRI oxidation was greater than that of P450IIC11/6, but the reverse was seen with respect to benzyl alcohol formation from toluene, indicating that P450IIC11/6 is relatively inactive towards benzene and TRI oxidation, but is primarily involved in toluene metabolism. P450IIB1/2 and P450IIC11/6 attacked all the metabolic positions studied, but only in the side-chain metabolism of toluene was their contribution significant, suggesting that these two isozymes are quite similar in function.
Nakajima
T
T
Department of Hygiene, Shinshu University School of Medicine, Matsumoto, Japan.
Wang
R S
RS
Elovaara
E
E
Park
S S
SS
Gelboin
H V
HV
Vainio
H
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001554:Benzene / Q000378:metabolism*; D002697:Chloral Hydrate / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology; D007527:Isoenzymes / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013379:Substrate Specificity; D014050:Toluene / Q000378:metabolism*; D014241:Trichloroethylene / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D007527:Isoenzymes; D014241:Trichloroethylene; D014050:Toluene; D000431:Ethanol; D002697:Chloral Hydrate; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D001554:Benzene; D010634:Phenobarbital