Xeroderma pigmentosum group A gene action as a protection factor against 4-nitroquinoline 1-oxide-induced tongue carcinogenesis

To test the hypothesis that nucleotide excision repair (NER) plays a protec tive role in chemical carcinogenesis in internal organs, xeroderma pigmento sum group A gene-deficient (XPAJ(-/-)) mice, heterozygous (XPA(+/-)) and wi ld-type (XPA(+/+)) mice were orally administered 0.001% 4-nitroquinoline 1- oxide (4NQO) in their drinking water and compared. After 50 weeks of 4NQO e xposure, tongue squamous cell carcinomas (SCCs) occurred in XPA(-/-) mice o nly, no tumors being observed in XPA(+/-) and XPA(+/+) animals. Of the XPA( -/-) mice 86% had tumors and 100% demonstrated multiple foci of dysplastic epithelium in the tongue. Accumulation of p53 protein was immunohistochemic ally detected in 56% of the SCCs, Mutational analysis of the p53 gene (exon s 4-10) in carcinoma DNA revealed missense mutations in exons 5 and 9 in fo ur of 20 samples. Our results clearly demonstrate that the NER gene XPA act s as a defensive factor against 4NQO-induced tongue carcinogenesis in vivo.