Modulatory mechanisms of chemical carcinogenesis: the role of the NADPH pool in the benzo(a)pyrene activation.
Human lymphocytes and human skin fibroblasts isolated in vitro from subjects carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase (G6PD) exhibit an 86-87% decrease of this enzymatic activity. This is coupled with 51% and 61% decreases of the NADPH/NADP+ ratio in the G6PD-deficient human lymphocytes (HL) and human skin fibroblasts (HSF), respectively. There also occurs a 63-67% decrease of the hexose monophosphate shunt (HMS) in the deficient cells. Incubation with 0.1 mM methylene blue stimulates the HMS of normal HL 15-fold and that of deficient lymphocytes only 2.4-fold. These figures are, respectively, 7 and 2.2 in the case of HSF. This behavior of G6PD-deficient HL and HSF is coupled with an increase of the resistance to the cell death induced by benzo(a)pyrene (BP). This effect is mimicked by the incubation of normal HSF with dehydroepiandrosterone (DEA) which strongly inhibits G6PD. In contrast, no differences between normal and deficient HSF occur as a result of the effect of methylnitrosourea (MNU), a carcinogen that does not need metabolic activation. The NADPH-cytochrome c (P450) reductase of G6PD-deficient HL and HSF homogenates becomes lower than that of controls when endogenous G6PD and exogenous glucose 6-phosphate (G6P) and NADP+ are used as a hydrogen donor system in place of NADPH. Normal and G6PD-deficient HL, having comparable BP-hydroxylating activities, in the presence of exogenous G6P, NADP+, and G6PD, were studied to determine the effect of the absence of exogenous G6PD in the reaction system.(ABSTRACT TRUNCATED AT 250 WORDS)
D001564:Benzo(a)pyrene / Q000378:metabolism*; D001711:Biotransformation; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000378:metabolism; D006801:Humans; D008297:Male; D009153:Mutagens / Q000378:metabolism; D009249:NADP / Q000502:physiology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000032:analysis; D009374:Neoplasms, Experimental / Q000139:chemically induced; D010427:Pentose Phosphate Pathway
D009153:Mutagens; D001564:Benzo(a)pyrene; D009249:NADP; D009251:NADPH-Ferrihemoprotein Reductase