Potent mutagenic potential of 4-methylquinoline: metabolic and mechanistic considerations.
4-Methylquinoline (4-MeQ) showed an extraordinarily potent mutagenicity when compared to quinoline and isomeric methylquinolines. The major metabolite of 4-MeQ was 4-hydroxymethylquinoline, which was not mutagenic under the assay condition employed. Deuteration of the methyl group of 4-MeQ resulted in a decrease in the amount of the hydroxymethyl metabolite and an increase in mutagenicity, indicating that hydroxylation of the substituent methyl group is a detoxication process. A 3-chloro derivative of 4-MeQ was proven to be non-mutagenic. 4-Ethyl-quinoline, as well as 4-hydroxymethylquinoline, was much less mutagenic than 4-MeQ. Taking account of the structure-mutagenicity relationship, a possible mechanism is proposed for the potent mutagenic potential of 4-MeQ.
Saeki
K
K
Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
Takahashi
K
K
Kawazoe
Y
Y
D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003903:Deuterium / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D016296:Mutagenesis; D009152:Mutagenicity Tests; D009153:Mutagens / Q000493:pharmacokinetics* / Q000633:toxicity*; D011804:Quinolines / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000378:metabolism
D009153:Mutagens; D011804:Quinolines; C057608:4-methylquinoline; D003577:Cytochrome P-450 Enzyme System; D003903:Deuterium