THE INDUCTION OF ATP ENERGIZED MITOCHONDRIAL VOLUME CHANGES BY SHOWDOMYCIN WHEN COMBINED WITH 4''8''-DIHYDROXY-1, 2, 5, 6-S.e-DIBENZ-9, 10-ANTHRAQUINONE, A METABOLITE OF THE CARCINOGENIC POLYNUCLEAR HYDROCARBON DIBENZ(A, H) ANTHRACENE

Abstract

The hydroxy quinone DI-OH-DBAQ [4'8'-dihydroxy-l, 2, 5, 6-dibenz-9, 10-anthraquinone] was shown to be a metabolite of the carcinogenic polynuclear hydrocarbon DBA [dibenz(a, h)anthracene] in 1953 by Heidelberger, Hadler and Wolf. DI-OH-DBAQ induces an ATP energized mitochondrial volume change in combination with the nonmercurial thiol reagent, showdomycin, [an antibiotic and an antitumor agent]. The parent carcinogen DBA when combined with showdomycin does not induce an ATP energized mitochondrial volume change. An appropriate concentration of DI-OH-DBAQ inhibits the ATP energized mitochondrial volume change induced by gramicidin in the presence of the permeant ions potassium and malate. The further addition of showdomysin reinstates the effect of gramicidin. Thus DI-OH-DBAQ exposes the strategically located pivotal mitochondrial thiol group which occupies the position between the cycle which meshes with the respiratory chain and a cycle which meshes with ATP. In these in vitro studies DIOH- DBAQ bears the same relationship to DBA that N-hydroxy-N-acetyl-2-aminofluorene bears to N-acetyl-2-aminofluorene an aromatic amide which is also a carcinogen. DI-OH-DBAQ is an uncoupling agent rather than a respiratory inhibitor as DI-OH-DBAQ stimulates mitochondrial respiration and induces the mitochondrial hydrolysis of adenosine-5'-triphosphate [ATPase activity]. These observations broaden the support for our hypothesis of oxidative phosphorylation (1961), the experimental confluence of oxidative phosphorylation with carcinogenesis and our unitary hypothesis for carcinogenesis (1971).