A requirement of Pi for the transitory uncoupling of rat liver mitochondria by hydrazine, when beta-hydroxybutyrate is the substrate.
We have recognized an experimental confluence between oxidative phosphorylation and chemical carcinogenesis and, therefore, became interested in the mitochondrial target of hydrazine, which is not only a potential environmental hazard as a carcinogen but is also a likely metabolite of many drugs. Hydrazine induced a Pi dependent transitory uncoupling of rat liver mitochondria when beta-hydroxybutyrate was the substrate. Uncoupling was inhibited by rutamycin; accordingly, the mitochondrial target for nucleophilic hydrazine is an electrophilic site, presumably involving activated Pi. The protective action of ATP2, ADP, PPi and Mg++ was attributed to a conformational change of the phosphorylating enzyme which participated in oxidative phosphorylation. In a mitochondrial system which included ATP gramicidin potassium ion and sulfate, hydrazine, acting as a large cation but not as a nucleophile, blocked mitochondrial swelling and the increment in ATPase activity associated with potassium ion. These data in conjunction with our previous reports dealing with other carcinogens and certain of their derivatives also contribute to an experimental confluence between oxidative phosphorylation and chemical carcinogenesis and are compatible with toxic effects of hydrazine on mitochondria observed previously by others.
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000641:Ammonia / Q000494:pharmacology; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D004140:Dinitrophenols / Q000494:pharmacology; D006096:Gramicidin / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology*; D006885:Hydroxybutyrates / Q000378:metabolism*; D066298:In Vitro Techniques; D008274:Magnesium / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010710:Phosphates / Q000494:pharmacology*; D051381:Rats; D012427:Rutamycin / Q000494:pharmacology; D014475:Uncoupling Agents
D004140:Dinitrophenols; D006834:Hydrazines; D006885:Hydroxybutyrates; D010710:Phosphates; D014475:Uncoupling Agents; D006096:Gramicidin; D012427:Rutamycin; D000244:Adenosine Diphosphate; D000968:Antimycin A; D000641:Ammonia; D000255:Adenosine Triphosphate; D008274:Magnesium