The mitochondrial activation of sulfate and arsenate and their role in carcinogenesis.
Sulfate substitutes for phosphate in the transitory uncoupling of rat liver mitochondria induced by hydrazine when beta-hydroxybutyrate is the substrate. A high level of sulfate in the absence of added phosphate induces a pseudo state three of the mitochondria. Uncoupling is inhibited by rutamycin. Thus sulfate is activated by the mechanism usually utilized by phosphate, and the target for hydrazine is the bond holding electrophilic sulfate. ATP, ADP, PPi, and Mg++ protect against hydrazine, presumably by causing a conformational change of the phosphorylating enzymes which participate in oxidative phosphorylation. Arsenate also could substitute for phosphate in the transitory uncoupling induced by hydrazine. Uncoupling is again inhibited by rutamycin; thus arsenate is also activated by the enzymic mechanism usually utilized by phosphate. Since sulfate is known to enhance the carcinogenicity of certain carcinogens, these results expand the experimental confluence between oxidative phosphorylation and chemical carcinogenesis and also serve to explain at least in part the "toxic" effects of sulfate. Because of the analogous results with arsenate and sulfate, it is suggested that arsenate, like sulfate, may enhance the carcinogenicity of other carcinogens. The data are compatible with epidemiological studies which implicate some role in carcinogenesis for sulfate (often measured as a sulfur dioxide equivalent) and arsenate.
D000818:Animals; D001149:Arsenates / Q000494:pharmacology*; D001151:Arsenic / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010710:Phosphates / Q000494:pharmacology; D051381:Rats; D013431:Sulfates / Q000494:pharmacology*
D001149:Arsenates; D002273:Carcinogens; D006834:Hydrazines; D010710:Phosphates; D013431:Sulfates; D001151:Arsenic