DICHLOROACETIC ACID PRETREATMENT OF MALE AND FEMALE RATS INCREASES CHLOROFORM METABOLISM IN-VITRO

The role of metabolism in dichloroacetic acid (DCA) potentiation of CH Cl3 hepatotoxicity was investigated. Male and female Sprague-Dawley ra ts 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 (CHCl3)-C-14, met abolism was measured in vitro. The binding of (CHCl3)-C-14-derivatives to microsomal proteins and lipids was increased 65 and 100%, respecti vely, in DCA-treated rats compared to their respective NaCl-treated co ntrols. The formation of CO2 (nmol (CO2)-C-14/incubation) was signific antly elevated in DCA-treated rats compared to controls (10.4 vs 6.3 i n males; 10.8 vs 6.1 in females). DCA treatment decreased the apparent Michaelis constant (K-m app) for conversion of (CHCl3)-C-14 to (CO2)- C-14 in rats (0.665 vs 0.415 mM in males, P < 0.05; 0.161 vs 0.081 in females). (CO2)-C-14 production and C-14 binding were observed under N -2 atmosphere, indicating that reactive metabolites of (CHCl3)-C-14 we re formed by oxidation as well as reduction. Male and female rats meta bolized CHCl3 differently. The K-m app for CO2 production was up to 5- fold higher in the males than in the females, regardless of DCA treatm ent. Inhibition by SKF 525-A and piperonyl butoxide was gender depende nt in both control and DCA-treated groups. The results showed, that in creased bioactivation of CHCl3 by DCA treatment is one element in the DCA-CHCl3 interaction. (C) 1997 Elsevier Science Ireland Ltd.