Characterization of cytochrome P450 2E1 activity by the [14C]nitrosodimethylamine breath test.
The objective of this study was to measure the rate of demethylation of nitrosodimethylamine in vivo in the rat and determine its value to assess CYP2E1 activity in intact animals. Nitrosodimethylamine labeled with 14C on both methyl groups was administered to rats and exhaled 14CO2 was collected during 2-3 h. The nitrosodimethylamine breath test was increased by inducers of CYP2E1, such as ethanol (+139%) and 4-methylpyrazole (+115%), and decreased by the inhibitor diallyl sulfide (-53%). In addition, the nitrosodimethylamine breath test was not changed significantly by inducers specific for other cytochrome P450 such as beta-naphthoflavone, dexamethasone, and phenobarbital. The specificity of the induction by 4-methylpyrazole and of the inhibition by diallyl sulfide for CYP2E1 was determined using the [14C]caffeine (CYP1A2), [14C]aminopyrine (CYP2C11), and [14C]erythromycin (CYP3A2) breath tests. 4-Methylpyrazole treatment caused a small increase of the caffeine (+33%) and aminopyrine (+9%) breath tests and no change of the erythromycin breath test. Diallyl sulfide treatment led to a small decrease of the caffeine breath test (-33%) and of the aminopyrine breath test (-13%) but a 23% increase of the erythromycin breath test. It is concluded that the [14C]nitrosodimethylamine breath test is useful to assess CYP2E1 activity in vivo in the rat.
Centre hospitalier de l'Université de Montréal and Département de pharmacologie, Faculté de médecine, Université de Montréal, Québec, Canada.
M C
MC
Bastien
J P
JP
Villeneuve
D000498:Allyl Compounds / Q000494:pharmacology; D000818:Animals; D001944:Breath Tests; D002250:Carbon Radioisotopes; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis / Q000378:metabolism*; D004128:Dimethylnitrosamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000077604:Fomepizole; D007700:Kinetics; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D013440:Sulfides / Q000494:pharmacology
D000498:Allyl Compounds; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D013440:Sulfides; C038491:allyl sulfide; D000077604:Fomepizole; D019392:Cytochrome P-450 CYP2E1; D004128:Dimethylnitrosamine