Low synthesis of retinoic acid due to impaired cytochrome P450 1a1 expression in mouse xeroderma pigmentosum fibroblasts

New tumor formation was suppressed by retinoic acid (RA) administration in xeroderma pigmentosum (XP) patients who have a defect in nuclear excision r epair. However, the inhibition is not due to enhanced removal of UV-damaged DNA. These results prompted us to investigate: whether or not RA metabolis m is abnormal in XP fibroblasts and what the underlying mechanism is. Compa red with wild type fibroblasts, low activities of RA synthesis were determi ned on HPLC in mouse fibroblasts lacking XP I:roup A (XPA) gene and UV-indu ced XPA deficient cancer cells. Moreover, we observed an impaired expressio n of cytochrome P450 1a1 in XPA deficient fibroblasts by RT-PCR and a decre ased expression of retinoic acid receptor gamma in XPA deficient cancer cel ls by Western blotting. Finally, pre-treatment of RA isoforms significantly protected the XPA deficient fibroblasts from UV-induced death. These resul ts suggest that decreased structure activity RA synthesis, resulting from i mpaired mRNA expression of cytochrome P450 1a1 may, at least together with UV irradiation, involve in skin carcinogenesis in XP patients. (C) 2001 Els evier Science Ltd. All rights reserved.