Metabolism of a heterocyclic amine colon carcinogen in young and old rats.
The incidence of colon cancer increases with age, and this may be related to altered metabolism and disposition 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 disposition and metabolism of IQ changes with age, comparing young (3-month) and old (22- to 24-month) male F344 rats. Animals were treated with vehicle or beta-naphthoflavone (BNF), an inducer of drug-metabolizing cytochromes P450. Disposition and metabolism of IQ were determined after i.p. injection of radiolabeled IQ. Urinary IQ metabolites were identified and quantitated by high-performance liquid chromatography and mass spectroscopy. In BNF-treated animals, total radiolabeled IQ excretion by old rats was less than half that of young rats. Binding of radiolabeled IQ metabolites by the old kidney was 10 times higher than that of 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.
Armbrecht
Harvey J
HJ
Geriatric Center (11G-JB), St. Louis VA Medical Center, St. Louis, MO 63125, USA. hjarmbrec@aol.com
Lakshmi
Vijaya M
VM
Wickstra
Jason
J
Hsu
Fong Fu
FF
Zenser
Terry V
TV
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D020719:Glucuronides / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007422:Intestines / Q000201:enzymology; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008297:Male; D015394:Molecular Structure; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D051381:Rats; D011916:Rats, Inbred F344; D013463:Sulfuric Acid Esters / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D019324:beta-Naphthoflavone / Q000494:pharmacology
D002250:Carbon Radioisotopes; D002273:Carcinogens; D020719:Glucuronides; D011804:Quinolines; D013463:Sulfuric Acid Esters; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System