Effect of exposure to four organic solvents on hepatic cytochrome P450 isozymes in rat.
Changes of cytochrome P450 isozymes in livers of rats after exposure to four solvents at 4000 ppm for 6 h, were studied by enzyme assays and immunochemical detection using antibodies to cytochrome P450 isozymes. Toluene, benzene and trichloroethylene (TRI) exposure resulted in a significant increase in the activities of nitrosodimethylamine demethylase (152%, 134% and 118%) and 7-pentoxyresorufin O-depentylase (14-, 5- and 2.5-fold), respectively. 1,1,1-Trichloroethane (TCE) showed little effect on the activities of the enzymes. Anti-CYP2E1 and anti-CYP2B1/2 inhibitable activity of toluene side-chain oxidase was significantly enhanced in toluene-, benzene- and TRI-treated rats. Anti-CYP2C11 inhibitable activity was greatly reduced as compared with control. The change in CYP2E1 and CYP2C11 was confirmed by the increase and decrease in the activities inhibited by 4-methylpyrazole and cimetidine, respectively. Western blot analysis revealed that the increase in peak area of bands recognized by anti-CYP2E1 was consistent with toluene inhibition results. CYP2B1/2 was not detectable in control rats, but it was strongly induced by toluene, followed by benzene and TRI. Some increases in the peak areas of bands recognized by anti-CYP2A1 and CYP-4A1 were also observed in the three solvents exposed rat microsomes. Little immunoreactivity was found with anti-CYP1A1 in all microsomes, and no obvious change in peak area of bands recognized by anti-CYP3A and anti-CYP2C13 was observed. TCE exposure showed little effect on these bands. The formation of phenol and hydroquinone from benzene was enhanced to different degree by toluene, benzene and TRI. The hydroxylation of testosterone at 6 beta and 7 alpha was increased by benzene, and benzene and TRI, respectively. However, the metabolism at 16 alpha and 2 alpha was profoundly suppressed by the solvents except TCE. These results showed that the four solvents have different effects on specific cytochrome P450 isozymes and on the metabolism of both endogenous and exogenous substances.
Wang
R S
RS
Department of Occupational Diseases, National Institute of Industrial Health, Kawasaki, Japan.
Nakajima
T
T
Tsuruta
H
H
Honma
T
T
D000818:Animals; D001554:Benzene / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D007527:Isoenzymes / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012997:Solvents / Q000494:pharmacology; D014050:Toluene / Q000378:metabolism / Q000494:pharmacology*; D014240:Trichloroethanes / Q000494:pharmacology; D014241:Trichloroethylene / Q000494:pharmacology
D007527:Isoenzymes; D012997:Solvents; D014240:Trichloroethanes; C024566:1,1,1-trichloroethane; D014241:Trichloroethylene; D014050:Toluene; D003577:Cytochrome P-450 Enzyme System; D001554:Benzene