The anomaly of pyridine nucleotide synergism in carbon tetrachloride metabolism.
Carbon tetrachloride metabolism was examined in hepatic microsomes isolated from control and phenobarbital-treated Sprague-Dawley rats to determine the mechanism of pyridine nucleotide synergism. An NADPH generator increased metabolism two fold as determined by lipid peroxidation. Addition of NADH to the reaction system did not alter the maximum velocity, but did decrease the Km for NADPH from 61 microM to 7.6 microM in control and from 21 microM to 6.3 mM PB microsomes. Addition of NAD+ produced an increase in metabolism similar to NADH. Substrates and competitive inhibitors of nucleotide pyrophosphatase also enhanced CCl4 metabolism. A high correlation (r = 0.947) was indicated between the percent inhibition of nucleotide pyrophosphatase and the percent synergism of NADPH-catalyzed CCl4 metabolism. Thus, pyridine nucleotide synergism in CCl4 metabolism appears to result from the increased availability of NADPH produced by a decreased degradation of the NADPH by the nucleotide pyrophosphatase.
Tortoriello
P J
PJ
Department of Pharmacology and Nutrition, University of Southern California, School of Medicine, Los Angeles 90033.
Riebow
J F
JF
Advani
S
S
Bidlack
W R
WR
D000818:Animals; D002251:Carbon Tetrachloride / Q000378:metabolism*; D004357:Drug Synergism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009249:NADP / Q000494:pharmacology*; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013379:Substrate Specificity
D009249:NADP; D002251:Carbon Tetrachloride; D011755:Pyrophosphatases; C021899:nucleotide pyrophosphatase