Monoclonal antibody-directed assessment of toluene induction of rat hepatic cytochrome P450 isozymes.
Cytochrome P450 isozymes induced in rat liver by a range of concentrations of toluene were studied with monoclonal antibodies (MAbs) to specific P450 isozymes and by enzyme assays. Nitrosodimethylamine demethylase activity was significantly increased in microsomes from rats exposed to more than 1000 ppm of toluene, an increase that was dose-dependent. Anti-CYP2E1 significantly inhibited the metabolism of toluene to benzyl alcohol (BA) by about 50%, in microsomes from 1000 to 4000 ppm toluene-exposed rats, at low substrate concentration (0.2 mM). With anti-CYP2B1/2, the rate of BA formation was decreased by 15-17% in microsomes from rats of 2000 and 4000 ppm toluene exposures at high substrate concentration (5.0 mM). On the other hand, anti-CYP2C11/6 inhibited the rate of formation of BA in all of the microsomes, but the extent of inhibition was progressively decreased from 55% in control to 33% in 4000 ppm exposure. Immunoblot analysis with anti-CYP2E1 and anti-CYP2B1/2 revealed stronger immunoreactive bands in microsomes from rats exposed to more than 1000 and 2000 ppm of toluene, respectively. Stronger bands were also observed in microsomes from rats of 2000-4000 ppm toluene exposures with anti-CYP3A1/2, but no immunoreactivity appeared with anti-CYP1A1/2. These results suggest that toluene induces CYP2E1, CYP2B1/2 and CYP3A1/2, but reduces CYP2C11/6, and has no effect on CYP1A1/2.
Wang
R S
RS
Department of Hygiene, Shinshu University School of Medicine, Matsumoto, Japan.
Nakajima
T
T
Park
S S
SS
Gelboin
H V
HV
Murayama
N
N
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D019905:Benzyl Alcohol; D001592:Benzyl Alcohols / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D007527:Isoenzymes / Q000096:biosynthesis* / Q000276:immunology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D010088:Oxidoreductases / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014050:Toluene / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D001592:Benzyl Alcohols; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D014050:Toluene; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D019905:Benzyl Alcohol