480 5. QUINONES 



Schulz and Goss (1956) demonstrated an in vivo depression of the incor- 

 poration of Pj^2 into ATP in liver and heart following the intraperitoneal 

 injection of menadione at 110-120 mg/kg, and felt that this indicated an 

 uncoupling action which might be responsible for the toxicity of menadione. 

 Actually no evidence for uncoupling was presented, and no reduction in 

 the P:0 ratio of liver mitochondria obtained from poisoned animals was 

 noted. Parmar and Lowenthal (1962) also could find no uncoupling in liver 

 mitochondria after hemorrhagic doses of the vitamin K^ antagonist, 2- 

 chloro-3-phytyl-l,4-naphthoquinone, so it appears that the reduction of 

 prothrombin synthesis is not related to uncoupling, although one must 

 admit the possibility that the antagonist was lost during the preparation 

 of the mitochondria. There has been no clear-cut evidence for vmcoupling 

 by the simpler quinones, such as p-benzoquinone and 1,4-naphthoquinone, 

 and indeed Ernster et al. (1963) detected no significant effects of these on 

 the P:0 ratio of liver mitochondria with glutamate as the substrate. The 

 ATP:P, exchange reaction in liver mitochondria is slightly stimulated 

 by menadione at 0.00001 0.0001 mM and inhibited 10% at 0.01 mM, 

 24% at 0.1 mM, and 58% at 1 mM (Dallam and Hamilton, 1964). The 

 2,4-dinitrophenol-activated ATPase activity is also inhibited. 



Despite the fact that menadiol is oxidized with a P:0 ratio of 0.2 by 

 an enzyme system from Azotohacter vinelandii, it uncouples the phosphoryl- 

 ation associated with the oxidation of NADH (Schils et al., 1960). It is 

 interesting that lapachol competitively inhibits the phosphorylation during 

 menadiol oxidation, but this does not necessarily indicate that a com- 

 petitive action is exerted on the normal system. However, lapachol com- 

 petitively prevents the reactivation of the irradiated mycobacterial system 

 by vitamin Kj (Brodie and Ballantine, 1960). The strong inhibitions exerted 

 by Qo and 6-Br-Qo, discussed in the preceding paragraph, are not compet- 

 itive since they cannot be reversed by active coenzyme Q analogs (Smith 

 and Lester, 1961). Thus there is so far very meager evidence for truly 

 competitive inhibition by the quinones. Several have suggested an electron- 

 shunting mechanism and certainly some nonphosphorylating pathways 

 are known, as the menadione bypass of vitamin Kj (Brodie, 1964), and it 

 is likely that this is important in some instances, but again we have little 

 direct evidence. Smith and Lester (1961) suggested that the uncouphng 

 action of Qo and 6-Br-Qo is at least partially due to shunting electrons 

 around a phosphorylating step, but they also favored the idea that reac- 

 tion with SH groups may contribute to this, as did Jacobs and Crane 

 (1960). It is clear that our knowledge of this aspect of the actions of qui- 

 nones is rudimentary and much remains to be done in this important field. 



