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Age-related changes in biotransformation of azoxymethane and methylazoxymethanol in vitro
T F McMahon1, J O Peggins, M M Centra
1Department of Pharmacology and Toxicology, University of Maryland, Baltimore.
Abstract:
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.
Insights
Aging reduces the liver
Area of Science:
- Toxicology
- Biochemistry
- Gerontology
Background:
- Azoxymethane (AZO) is a colon carcinogen.
- Age-related metabolic changes can affect carcinogen biotransformation and risk.
- Fischer 344 rats are a common model for aging studies.
Purpose of the Study:
- To investigate age-related changes in the metabolism of azoxymethane (AZO) and its metabolite methylazoxymethanol (MAM) in male Fischer 344 rats.
- To determine the role of hepatic hydroxylation and colonic Phase I metabolism in AZO/MAM biotransformation across different age groups.
- To explore the potential involvement of colonic glucuronyltransferase in MAM biotransformation.
Main Methods:
- Comparison of hepatic AZO to MAM conversion and colonic MAM metabolism by alcohol dehydrogenase (ADH) in young, middle-aged, and old male Fischer 344 rats.
- Measurement of hepatic cytochrome P-450 content.
- Assessment of MAM inhibition of colonic 4-methylumbelliferone glucuronyltransferase activity.
Main Results:
- A significant decrease in hepatic conversion of AZO to MAM was observed in old rats compared to young rats.
- Hepatic cytochrome P-450 content also decreased with age.
- No age-related differences were found in the colonic metabolism of MAM by ADH.
- MAM exhibited non-competitive inhibition of colonic glucuronyltransferase, suggesting it is not a substrate for this enzyme.
Conclusions:
- Ageing alters AZO and MAM biotransformation in male Fischer 344 rats, specifically reducing hepatic hydroxylation.
- Reduced hepatic metabolism of AZO to MAM in older rats may lead to decreased carcinogenic potential.
- Colonic glucuronyltransferase is unlikely to be involved in the conjugation of MAM.