Interactions of glucose-6-phosphate dehydrogenase deficiency with drug acetylation and hydroxylation reactions.
We hypothesize that the bimodal distribution of hemolytic response by G6PG-deficient individuals to particular drugs such as sulfones may be due to the genetically determined acetylation rate of those drugs. Since metabolism, e.g., hydroxylation, may be required for these drugs to become hemolytic, genetically and environmentally determined variation in hydroxylation of a drug may also contribute to this variability in hemolytic response. To test the possibilities that acetylation and hydroxylation alter the hemolytic potential of these drugs, we incubated G6PG-deficient and normal red cells with mouse liver microsomes at two states of hydroxylase activity (uninduced and induced), an NADPH-generating system, and acetylated or unacetylated drug. We then measured GSH depletion in the cells as an indicator of prelytic cell damage. We found that in the presence of induced (high hydroxylase activity) microsomes, thiazolsulfone (Promizole) or DDS in unacetylated form caused the highest level of GSH depletion in G6PD-deficient red cells. Acetylation protected against GSH depletion. The specificity of the hydroxylation reaction in producing marked GSH depletion was shown by the protective effect of a specific hydroxylation inhibitor. Our results indicate that G6PD-deficient, genetically slow acetylators, having high microsomal activity, would be most susceptible to Promizole- or DDS-induced hemolysis, compared to other metabolic phenotypes. In addition, the bimodality in hemolytic response to Promizole probably corresponds to the bimodal distribution of acetylator phenotype in the population.
D000107:Acetylation; D000818:Animals; D003622:Dapsone / Q000494:pharmacology; D004912:Erythrocytes / Q000378:metabolism; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000032:analysis; D006461:Hemolysis; D006900:Hydroxylation; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D013450:Sulfones; D013844:Thiazoles; D003622:Dapsone; D005978:Glutathione; C009453:thiazosulfone