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.
Grossman
C P
CP
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison 53706.
Suttie
J W
JW
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D019735:Carbon-Carbon Ligases; D002733:Chlorophenols / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008025:Ligases / Q000037:antagonists & inhibitors*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011516:Prothrombin / Q000032:analysis / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014812:Vitamin K / Q000494:pharmacology*; D064417:Vitamin K Epoxide Reductases
D000925:Anticoagulants; D002733:Chlorophenols; D011725:Pyridines; D014812:Vitamin K; C003389:2,3,5,6-tetrachloro-4-pyridinol; C009408:tetrachlorophenol; D011516:Prothrombin; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; D008025:Ligases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase