Dose dependent inhibitory effects of dietary 8-methoxypsoralen on NNK-induced lung tumorigenesis in female A/J mice.
We have reported that pretreatment by stomach tube with 8-methoxypsoralen (methoxsalen; 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 (Cancer Res. 2003). Here, we examined inhibitory effects with administration in the diet. When the mice were 7 weeks of age, they received dietary supplementation with 8-MOP at concentrations of 1, 10 or 100 ppm for 3 days prior to a single dose of NNK (2mg/0.1 ml saline/mouse, i.p.) or an equal volume of saline (vehicle control). The experiment was terminated 16 weeks after the first 8-MOP treatment and lung proliferative lesions were analyzed. The incidences and multiplicities in the 8-MOP 100 ppm-treated group were significantly reduced as compared with values for the NNK alone group (P<0.001). Multiplicities of NNK-induced lung proliferative lesions were also reduced in a dose dependent manner (Spearman rank correlation coefficient; rho=-0.806, correction P<0.0001). Mouse CYP2A4 and CYP2A5 differ from each other only 11 amino acids, and are closely related to the human CYP2A6. One hour after the last of three daily doses of 8-MOP (0.5, 5 or 50mg/kg body weight in 0.2 ml corn oil, given by stomach tube) or an equal volume of corn oil (vehicle control), given to the mice at 7 weeks of age, isolation of lung and liver RNAs demonstrated no effects on CYP2A4 and CYP2A5 mRNA levels with 8-MOP. In conclusion, the results of this study showed that clear dose response inhibitory effects of 8-MOP on NNK-induced lung tumorigenesis in female A/J mice fed diets containing 8-MOP, due to inhibition of enzyme activity of CYP2A4 and CYP2A5, rather than their gene expression.
Takeuchi
Hijiri
H
Onco-Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Saoo
Kousuke
K
Matsuda
Yoko
Y
Yokohira
Masanao
M
Yamakawa
Keiko
K
Zeng
Yu
Y
Miyazaki
Masafumi
M
Fujieda
Masaki
M
Kamataki
Tetsuya
T
Imaida
Katsumi
K
D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000188:drug therapy*; D008730:Methoxsalen / Q000008:administration & dosage*; D051379:Mice; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000187:drug effects; D009602:Nitrosamines / Q000633:toxicity*; D012333:RNA, Messenger / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000187:drug effects
D002273:Carcinogens; D009602:Nitrosamines; D012333:RNA, Messenger; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C460223:Cyp2a4 protein, mouse; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D008730:Methoxsalen