Lack of modifying potential of 8-methoxypsoralen in the promotion or progression stages of lung carcinogenesis in A/J female mice.
Pretreatment with 8-methoxypsoralen (8-MOP), a potent human CYP2A6 inhibitor, strongly suppresses lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice. Since it has been reported that CYP2A protein is highly expressed in NNK-induced lung adenomas and adenocarcinomas, potential anticancer properties of 8-MOP in female A/J mice were examined subsequent to initiation. The agent was administered at 100 ppm levels in the diet during the promotion phase (experimental weeks 1-16) and progression phase (experimental weeks 16-32) and mice were sacrificed for histopathological examination of lung tumor development at 16 and 32 weeks after the initiation of NNK treatment (2 mg/0.1 ml saline/mouse, i.p.), respectively. Chemopreventive effects of 8-MOP were not observed in either experiment. In addition, no modifying effects on hepatic mRNA levels for CYP2A5, considered to be the mouse ortholog of human CYP2A6, were evident. On immunohistochemical analysis, the CYP2A protein was found to be overexpressed in all lung adenomas and adenocarcinomas, with or without 8-MOP. It can be concluded from the present data that 8-MOP at 100 ppm in the diet does not prevent mouse lung carcinogenesis when administered in the post-initiation phase.
Kuno
Toshiya
T
Onco-Pathology, Department of Pathology and Host-Defence, Faculty of Medicine, Kagawa University, Kagawa, Japan. kuno@med.kagawa-u.ac.jp
Yokohira
Masanao
M
Matsuda
Yoko
Y
Suzuki
Satoshi
S
Hashimoto
Nozomi
N
Yamakawa
Keiko
K
Saoo
Kousuke
K
Imaida
Katsumi
K
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008730:Methoxsalen / Q000494:pharmacology*; D051379:Mice; D009367:Neoplasm Staging; D009602:Nitrosamines / Q000633:toxicity
D004791:Enzyme Inhibitors; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D008730:Methoxsalen