Hydroxylation and dealkylation of methyl-n-butylnitrosamine and role of certain cytochrome P-450 isozymes in these reactions.
We studied the metabolism of methyl-n-butyl-nitrosamine (MBN), a carcinogen for the rat esophagus and liver. The 2-, 3- and 4-hydroxy derivatives were identified as new metabolites of MBN. In studies on tissue slices freshly removed from MRC-Wistar rats, MBN metabolism resembled that of the previously studied methyl-amylnitrosamine in the esophagus catalyzed 2- and 3- hydroxylation; liver, omega-1 hydroxylation; and lung, omega-hydroxylation of both nitrosamines. Liver microsomes from Sprague-Dawley rats catalyzed 2-, 3- and 4-hydroxylation of MBN, as well as the previously studied activating reactions of demethylation and debutylation. Phenobarbital induced all five reactions of MBN bh rat liver microsomes, especially debutylation; 3-methylhol-anthrene induced 3-hydroxylation and debutylation and isoniazid induced demethylation and debutylation. Monoclonal antibodies that inhibit specific cytochrome P-450 isozymes were used to identify the isozymes involved in each reaction. Antibody 4-7-1 appeared more specific than the previously used antibody 2-66-3 for inhibiting P-450 2B1 and/or 2B2. For the metabolism of both MBN and methylamylnitrosamine by rat liver microsomes, the antibody results indicated that P-450 2C11 mainly catalyzed demethylation and omega-1 hydroxylation, P-450 1A1 or 1A2 catalyzed 3-hydroxylation and debutylation or depentylation, P-450 2E1 produced demethylation and P-450 2B1 or 2B2 produced omega-1 hydroxylation, demethylation and debutylation or depentylation.
Huang
Q
Q
Eppley Institute for Research in Cancer, University of Nebraska, Omaha 68198-6805.
Wang
S
S
Chen
S C
SC
Babcook
D M
DM
Park
S S
SS
Gelboin
H V
HV
Mirvish
S S
SS
D000818:Animals; D002273:Carcinogens / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006900:Hydroxylation; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009602:Nitrosamines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D002273:Carcinogens; D007527:Isoenzymes; D009602:Nitrosamines; C034649:nitrosomethyl-N-butylamine; D003577:Cytochrome P-450 Enzyme System