Dichloroacetic acid pretreatment of male and female rats increases chloroform metabolism in vitro.
The role of metabolism in dichloroacetic acid (DCA) potentiation of CHCl3 hepatotoxicity was investigated. Male and female Sprague-Dawley rats were given three doses (09:00, 16:00 and 09:00 the next morning) of DCA (each 2.45 mmol/kg) by gavage. The rats were euthanized 3 h after the last dose, hepatic microsomes were prepared and 14CHCl3 metabolism was measured in vitro. The binding of 14CHCl3-derivatives to microsomal proteins and lipids was increased 65 and 100%, respectively, in DCA-treated rats compared to their respective NaCl-treated controls. The formation of CO2 (nmol 14CO2/incubation) was significantly elevated in DCA-treated rats compared to controls (10.4 vs 6.3 in males; 10.8 vs 6.1 in females). DCA treatment decreased the apparent Michaelis constant (Km app) for conversion of 14CHCl3 to 14CO2 in rats (0.665 vs 0.415 mM in males, P < 0.05; 0.161 vs 0.081 in females). 14CO2 production and 14C binding were observed under N2 atmosphere, indicating that reactive metabolites of 14CHCl3 were formed by oxidation as well as reduction. Male and female rats metabolized CHCl3 differently. The Km app for CO2 production was up to 5-fold higher in the males than in the females, regardless of DCA treatment. Inhibition by SKF 525-A and piperonyl butoxide was gender dependent in both control and DCA-treated groups. The results showed, that increased bioactivation of CHCl3 by DCA treatment is one element in the DCA-CHCl3 interaction.
Yang
H M
HM
Department of Pharmacology and Toxicology, Health Sciences Center, West Virginia University, Morgantown 26506-9223, USA.
Davis
M E
ME
D000818:Animals; D001711:Biotransformation; D002245:Carbon Dioxide / Q000378:metabolism; D002725:Chloroform / Q000378:metabolism* / Q000633:toxicity; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D005260:Female; D005978:Glutathione / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors
D002245:Carbon Dioxide; D002725:Chloroform; D003999:Dichloroacetic Acid; D011335:Proadifen; D005978:Glutathione