Vitamin K-dependent carboxylase: inhibitory action of polychlorinated phenols

The compound 2,3,5,6-tetrachloropyridinol (TCP) is a known inhibitor of the rat liver vitamin K-dependent carboxylase. A series of chlorinated phenols was also assayed for their abilities to inhibit the carboxylase in vitro. One compound, 2,3,5,6-tetrachlorophenol, was as potent a carboxylase inhibitor as TCP (I50 = 5-10 microM). Four compounds with substituents in the 4 position exhibited I50 values 5-20 times greater than the identical structures with hydrogen in the 4 position. Tetrachloroanisol, the methyl ether of tetrachlorophenol, did not inhibit the reaction, and inhibition by 2,5-dichlorophenol, which has a pKa of 7.2, was pH dependent, suggesting that the anionic form of the phenol is the inhibitor. No other direct structure/function correlations were evident. Previous reports have shown that TCP inhibition of the carboxylase is not competitive versus vitamin K in vitro, but that in vivo antagonism by TCP can be reversed with vitamin K. Rats given 40 mg/kg TCP had decreased plasma prothrombin levels and increased amounts of liver microsomal prothrombin precursors, whereas rats injected with 1 mg vitamin K 24 hr before the TCP injection had normal levels of both. Vitamin K administration could not overcome completely the effects of 100 mg/kg TCP. Animals injected with TCP had increased levels of vitamin K 2,3-epoxide in the liver, which would be consistent with a partial inhibition of the microsomal vitamin K-epoxide reductase by this anticoagulant.