Modulatory effect of glucose-6-phosphate dehydrogenase deficiency on benzo(a)pyrene toxicity and transforming activity for in vitro-cultured human skin fibroblasts.
Human skin fibroblasts isolated in vitro from subjects carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase exhibit an 85% decrease of this enzymatic activity. There is a 26% and a 94% decrease of the hexose monophosphate shunt and of the reduced nicotinamide adenine dinucleotide phosphate/nicotinamide adenine dinucleotide phosphate ratio, respectively. Incubation with 0.1 mM methylene blue activates the hexose monophosphate shunt 7 times that of normal fibroblasts and only 2.2 times that of glucose 6-phosphate-deficient cells. This behavior is coupled with an increase of the resistance to cell death induced by benzo(a)pyrene, a carcinogen, the activation of which proceeds through a reduced nicotinamide adenine dinucleotide phosphate-dependent arene oxide formation. In contrast, no difference between the normal and the deficient fibroblasts exists as regards the toxic effect of methylnitrosourea, a carcinogen that does not need metabolic activation. A growth-retarding effect of benzo(a)pyrene was observed in both normal and deficient cells during 9 days in vitro. This effect is lower in the fibroblasts carrying the Mediterranean glucose-6-phosphate dehydrogenase variant. Glucose-6-phosphate dehydrogenase deficiency protects human fibroblasts against the benzo(a)pyrene-induced in vitro transformation. This effect is mimicked by the incubation of normal fibroblasts with dehydroepiandrosterone, a strong inhibitor of glucose-6-phosphate dehydrogenase. The deficiency of this enzymatic activity, either genetically transmitted or induced by dehydroepiandrosterone, is coupled with a reduced rate of benzo(a)pyrene conversion to water-soluble metabolites by human skin fibroblasts.
D001564:Benzo(a)pyrene; D001580:Benzopyrenes / Q000378:metabolism / Q000633:toxicity*; D001711:Biotransformation; D002273:Carcinogens / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D005347:Fibroblasts / Q000502:physiology; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000503:physiopathology*; D006801:Humans; D007700:Kinetics; D008297:Male; D012016:Reference Values; D012867:Skin / Q000503:physiopathology*
D001580:Benzopyrenes; D002273:Carcinogens; D001564:Benzo(a)pyrene; D005954:Glucosephosphate Dehydrogenase