Received for publication October 27, 2006.
Revised January 19, 2007.
Accepted for publication January 23, 2007.

Metabolism of a Heterocyclic Amine Colon Carcinogen in Young and Old Rats

Abstract

Colon cancer increases with age, and this may be related to altered metabolism and deposition of carcinogens. One such carcinogen implicated in colon cancer is the heterocyclic amine found in well-done meat, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). The purpose of these studies was to determine whether the deposition and metabolism of IQ changes with age, comparing young (3 month) and old (22-24 month) male F344 rats. Animals were treated with vehicle or beta napthoflavone (BNF), an inducer of drug-metabolizing cytochrome P450s. Deposition and metabolism of IQ were determined after ip injection of radiolabeled IQ. Urinary IQ metabolites were identified and quantitated by HPLC and mass spectroscopy. In BNF-treated animals, total radiolabeled IQ excretion by old rats was less than half that of young. Binding of radiolabeled IQ metabolites by the old kidney was 10 times higher than the young. There were no age differences in intestinal and hepatic binding. There was a significant age-related increase in IQ conjugation to glucuronic acid and a decrease in conjugation to sulfate regardless of treatment. The induction of renal CYP1A1, a major P450 involved in IQ metabolism, by BNF did not change with age. Changes in IQ metabolism with age along with altered renal function may contribute to the decreased urinary excretion and increased renal binding of IQ and/or its metabolites seen in the old animals.

Key words: carcinogen metabolism, chemical carcinogenesis, CYP1A, glucuronidation, HPLC, mass spectrometry, renal disposition, renal elimination, renal toxicity, sulfate conjugation