Previously, we demonstrated that
8-methoxypsoralen (
methoxsalen), a potent human
cytochrome P450 2A6 (CYP2A6) inhibitor, strongly suppresses lung
adenoma induction by
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice. In the present study, we examined the inhibitory effects of
methoxsalen on the development of
lung adenocarcinomas, as well as on
adenomas and alveolar
hyperplasia. Female A/J mice were treated with
methoxsalen at doses of 12.5 or 1.25 mg/kg
body weight, administered by stomach tube once daily for 3 days. One hour after the final treatment, NNK was injected i.p. at a dose of 2 mg/mouse. The experiments were terminated 52 weeks after the first
methoxsalen treatment, and lung
adenomas and
adenocarcinomas were analyzed histopathologically. Pretreatment with
methoxsalen significantly reduced the incidence of
adenocarcinomas from 94.7 to 46.7% (12.5 mg/kg) and 44.4% (1.25 mg/kg), and their
tumor multiplicity from 4.68 to 0.87 (12.5 mg/kg) and 0.61 (1.25 mg/kg)
tumors/mouse. The
tumor multiplicity of
adenomas and
adenocarcinomas in the
methoxsalen-treated groups was significantly reduced from 12.47 to 5.67 (12.5 mg/kg) and 4.28 (1.25 mg/kg)
tumors/mouse. Approximately 60% of the
adenocarcinomas arose within
adenomas. In comparing the
methoxsalen + NNK and NNK alone groups, there was no significant difference in the frequency of such compound lesions, indicating that pretreatment with
methoxsalen did not suppress the eventual progression of
adenomas to
adenocarcinomas. These results clearly demonstrate that
methoxsalen, a potent human CYP2A6 inhibitor, inhibits not only lung
adenoma but also
adenocarcinoma development.