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.