Lack of modifying potential of 8-methoxypsoralen in the promotion or progression stages of lung carcinogenesis in A/J female mice

Abstract

Abstract. 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 NNKinduced 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.

Gender-dependent effects of gonadectomy on lung carcinogenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female and male A/J mice

“…of NNK ( 5 – 9 ). We also reported carcinogenic mechanisms and modifying effects of other factors using NNK-induced lung cancer animal models ( 10 – 15 ).…”

Dosimetry for lung tumorigenesis induced by urethane, 4-(<i>N</i>-methyl-<i>N</i>-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and benzo[a]pyrene (B[a]P) in A/JJmsSlc mice

“…Suppression of body weight gain was previously reported in female mice treated with a high dose of NNK. Because this effect became no longer statistically significant by 32 weeks, it was regarded as not being lethal 13 . In our study, the maximal suppression of body weight gain in the highest dose groups was approximately 10%, meeting the criteria for the maximally tolerated dose in a carcinogenicity study.…”

Dietary Phytochemicals as Potential Chemopreventive Agents against Tobacco-Induced Lung Carcinogenesis

“…Laboratory studies showed its effectiveness in chemoprevention of lung cancer Regarding the chemopreventive properties, 8-MOP was demonstrated to inhibit the CYP2A5-mediated metabolic activation of NNK in the mouse lung, leading to the prevention of NNK-induced adenoma [ 36 , 37 , 38 ]. However, 8-MOP in the diet of post-initiation phase does not prevent mouse lung carcinogenesis [ 107 ]. This effect is also confirmed in C57BL/6 mice that are induced by NNK [ 39 ].…”