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 repair. However, the inhibition is not due to enhanced removal of UV-damaged DNA. These results prompted us to investigate whether or not RA metabolism is abnormal in XP fibroblasts and what the underlying mechanism is. Compared with wild type fibroblasts, low activities of RA synthesis were determined on HPLC in mouse fibroblasts lacking XP group A (XPA) gene and UV-induced XPA deficient cancer cells. Moreover, we observed an impaired expression of cytochrome P450 1a1 in XPA deficient fibroblasts by RT-PCR and a decreased expression of retinoic acid receptor gamma in XPA deficient cancer cells by Western blotting. Finally, pre-treatment of RA isoforms significantly protected the XPA deficient fibroblasts from UV-induced death. These results suggest that decreased structure activity of RA synthesis, resulting from impaired mRNA expression of cytochrome P450 1a1 may, at least together with UV irradiation, involve in skin carcinogenesis in XP patients.
Ding
J
J
Department of Biochemistry, Kagawa Medical University, Kagawa, Japan.
Ichikawa
M
M
Furukawa
A
A
Tomita
S
S
Tanaka
K
K
Ichikawa
Y
Y
D000077556:Alitretinoin; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D051379:Mice; D010105:Oxygenases / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D050697:Retinal Dehydrogenase; D012177:Retinol-Binding Proteins / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000378:metabolism*; D051760:Xeroderma Pigmentosum Group A Protein
D004268:DNA-Binding Proteins; D018168:Receptors, Retinoic Acid; D012177:Retinol-Binding Proteins; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D000077556:Alitretinoin; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D019363:Cytochrome P-450 CYP1A1; D050697:Retinal Dehydrogenase