Age-related changes in biotransformation of azoxymethane and methylazoxymethanol in vitro.
1. Age-related changes in hepatic hydroxylation of azoxymethane (AZO) to methylazoxymethanol (MAM), as well as colonic phase I metabolism of MAM by alcohol dehydrogenase (ADH) were examined in young (2-4 months), middle-aged (12-14 months), and old (22-24 months) male Fischer 344 rats. In addition, the possibility that colonic glucuronyltransferase might be involved in the biotransformation of MAM was also investigated. 2. A significant decrease in hepatic conversion of AZO to MAM was found in old vs young rats, concomitant with a decrease in hepatic cytochrome P-450 content, while no age-related difference was found in the colonic metabolism of MAM by ADH. MAM inhibition of colonic 4-methylumbelliferone glucuronyltransferase was non-competitive, suggesting indirectly that colonic glucuronyltransferase is not involved in conjugation of MAM. 3. It is concluded that ageing in the male Fischer 344 rat results in alternations of AZO and MAM biotransformation which indicate that AZO may be less carcinogenic in older rats.
McMahon
T F
TF
Department of Pharmacology and Toxicology, University of Maryland, Baltimore.
Peggins
J O
JO
Centra
M M
MM
Weiner
M
M
D000375:Aging / Q000378:metabolism*; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000818:Animals; D001391:Azo Compounds / Q000493:pharmacokinetics*; D001397:Azoxymethane / Q000493:pharmacokinetics*; D001711:Biotransformation; D002273:Carcinogens; D003106:Colon / Q000201:enzymology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D006900:Hydroxylation; D006923:Hymecromone / Q000378:metabolism; D008297:Male; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D001391:Azo Compounds; D002273:Carcinogens; D005965:Glucuronates; D006923:Hymecromone; D008746:Methylazoxymethanol Acetate; D003577:Cytochrome P-450 Enzyme System; D000426:Alcohol Dehydrogenase; D014453:Glucuronosyltransferase; C030667:methylazoxymethanol; D001397:Azoxymethane