title: Inhibitory effect of dietary 4-ipomeanol on DNA adduct formation by the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in male CDF1 mice.
abstract: The food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is carcinogenic in the CDF1 mouse liver, lungs and stomach. IQ is activated to its ultimate carcinogenic form by N-hydroxylation, catalyzed principally by hepatic microsomal cytochrome P450IA2, and further esterification, resulting in the formation of N-(deoxyguanosin-8-yl)-IQ and other adducts. The furanoterpenoid 4-ipomeanol (IPO) is a naturally occurring pneumotoxin which exerts its specific toxicity in Clara cells of the lung after activation by microsomal cytochrome P450. Because IPO is activated in the liver by a cytochrome P450IA2 enzyme, we evaluated IPO as a possible chemopreventive agent by assessing its ability to inhibit IQ-DNA adduct formation in the CDF1 mouse. Mice were put on an AIN-76A diet with or without 0.075% IPO from day 0 to 54. IQ (0.01%) was added to the diets from day 22 to 41 and animals were killed (four animals/time point) on days 42, 44, 46, 48, 50 and 54. Blood (for white blood cell isolation), liver, lungs, stomach, small intestine, cecum, colon, kidneys, spleen and heart were collected for analysis of IQ-DNA adducts by 32P-post-labeling. During the 12 day period after cessation of IQ exposure (days 42-54) IQ-DNA adduct formation was significantly inhibited in the liver (33.6-46.4%), lungs (29.9-58.6%), stomach (33.2-51.5%) and white blood cells (24.5-63.7%), but not in the other organs. Except in the colon, adduct removal from organs during days 42-54 was relatively slow (36.0-81.9% of day 42 levels remaining on day 54, 9.4-16.7% in the colon), but the presence of IPO in the diet did not influence the rate of adduct removal. Measurement of hepatic microsomal ethoxyresorufin deethylase, an activity specific for cytochrome P450IA isozymes, showed that the enzyme could be inhibited (14.1-68.1%) by IPO (0.05-10.0 mM) in vitro. It is concluded that IPO inhibits IQ-DNA adduct formation in target organs of the CDF1 mouse and that IPO may act by inhibiting N-hydroxylation of IQ. It is therefore possible that IPO may be a candidate chemopreventive agent against IQ-induced carcinogenesis.
authors.affiliation: Department of Pathology, Medical College of Ohio, Toledo 43699, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Cummings
authors.forename: H A
authors.initials: HA
authors.lastname: Schut
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001711:Biotransformation; D001835:Body Weight / Q000187:drug effects; D002432:Cecum / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004032:Diet; D007421:Intestine, Small / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000201:enzymology*; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D009206:Myocardium / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D011804:Quinolines / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity*; D013154:Spleen / Q000378:metabolism; D013729:Terpenes / Q000008:administration & dosage / Q000494:pharmacology*; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; C096278:DNA-(2-amino-3-methylimidazo(4,5-f)quinoline) adduct; D009153:Mutagens; D011804:Quinolines; D013729:Terpenes; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; C001470:4-ipomeanol