Sister-chromatid exchange induction by metabolically activated retinoids in human diploid fibroblast cultures.
13-cis-Retinoic acid, retinyl-mthyl-ether, retinyl-phenyl-ether, retinyl-thio-ether and axerophthene each induced dose-dependent sister-chromatid exchanges (SCE) in human diploid fibroblasts. The functional relationship between retinoid concentration and SCE rate was similar in each of the 5 retinoids tested. The relationship reached a plateau at concentrations exceeding 8 micrograms/ml. alpha-Naphthoflavone (ANF), an inhibitor of P448-dependent mono-oxygenase, prevented the retinoid-induced increase of the SCE rate, but had no inhibitory effect in the presence of 4-nitroquinoline-1-oxide, an ultimate carcinogen. ANF did not reduce the spontaneously increased SCE rate in fibroblasts of patients with Bloom's syndrome. Retinoids failed to induce SCE in V79 Chinese hamster cells, which lack mono-oxygenase. Thus, we conclude that the retinoid-induced SCE rate increases independently of structural changes in the molecular side-chain ad that a metabolic activation of retinoids is required for SCE induction by cytochrome P448-dependent mono-oxygenase.
D000015:Abnormalities, Multiple / Q000235:genetics; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D003434:Crossing Over, Genetic / Q000187:drug effects*; D019388:Cytochrome P-450 CYP1A2; D003580:Cytochromes; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D015474:Isotretinoin; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D012867:Skin; D013329:Structure-Activity Relationship; D013684:Telangiectasis / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D001571:Benzoflavones; D003580:Cytochromes; D014801:Vitamin A; D014212:Tretinoin; C011512:alpha-naphthoflavone; D006899:Mixed Function Oxygenases; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; C027270:cytochrome P448-dependent mono-oxygenase; D015474:Isotretinoin