Pretreatment with 8-methoxypsoralen, a potent human CYP2A6 inhibitor, strongly inhibits lung tumorigenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in female A/J mice.
Human CYP2A6 has been recognized as being involved in the mutagenic activation of promutagens such as the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Methoxsalen (8-methoxypsoralen) was reported to inhibit CYP2A6. In the present study, the inhibitory effects of methoxsalen on NNK-induced lung tumorigenesis in female A/J mice were examined. Female A/J mice were treated with methoxsalen at doses of 50 or 12.5 mg/kg body weight, given by stomach tube, daily for 3 days. One h after the final treatment, NNK was injected i.p. at a dose of 2 mg/mouse. The experiments were terminated 16 weeks after the first methoxsalen treatment, and lung adenomas were analyzed. Pretreatment of methoxsalen significantly reduced tumor incidence from 93.8% to 16.7% (50 mg/kg) and 20.0% (12.5 mg/kg), and tumor multiplicity from 5.97 to 0.23 (50 mg/kg) and 0.25 (12.5 mg/kg) tumors/mouse. These results clearly demonstrated that methoxsalen, a potent human CYP2A6 inhibitor, is a strong chemopreventive agent against NNK-induction of lung tumorigenesis.
Takeuchi
Hijiri
H
Onco-Pathology, Department of Pathology and Host-Defense, Kagawa Medical University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Saoo
Kousuke
K
Yokohira
Masanao
M
Ikeda
Mico
M
Maeta
Hajime
H
Miyazaki
Masafumi
M
Yamazaki
Hiroshi
H
Kamataki
Tetsuya
T
Imaida
Katsumi
K
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D002273:Carcinogens / Q000037:antagonists & inhibitors*; D065637:Cytochrome P-450 CYP2A6; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D008730:Methoxsalen / Q000494:pharmacology*; D051379:Mice; D008805:Mice, Inbred A; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D009602:Nitrosamines / Q000037:antagonists & inhibitors*
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D008730:Methoxsalen