Dichloroacetic acid pretreatment of male and female rats increases chloroform-induced hepatotoxicity

Abstract

Dichloroacetic acid (DCA) and chloroform (CHCl 3) are both major by-products of drinking water chlorination and DCA increases the hepatotoxicity of CHCl 3. In this study, we further characterized this effect and investigated DCA-induced alterations of CHCl 3 disposition and metabolism as a possible mechanism for this interaction. Both adult male and female Sprague-Dawley rats were gavaged with three doses (09:00, 16:00 and 09:00 the next morning) of DCA (each 2.45 mmol/kg), then challenged with an i.p. injection of CHCl 3 (3.12 or 9.35 mmol/kg). Hepatic damage was assessed 24 h after CHCl 3 administration as increased alanine aminotransferase (ALT), ornithine carbomyl transferase (OCT) and bilirubin in plasma. In a separate experiment, rats were pretreated with DCA or were given 14CHCl 3 at the same dosages. The disposition of 14C in various tissues and covalent binding of 14CHCl 3-derivatives to liver proteins and lipids were determined 1 h later. CHCl 3-induced hepatotoxicity was significantly more severe in DCA-pretreated groups. ALT and OCT were more markedly elevated in DCA+CHCl 3 (3.12 mmol/kg) groups than NaCl+CHCl 3 animals. Plasma bilirubin content was elevated only in DCA+CHCl 3 groups and females were more susceptible to this effect. The responses of rats to DCA treatment were somewhat gender-different. DCA treatment increased total cytochrome P450 in females, but not in males. Hepatic glutathione concentration was elevated in males after DCA treatment, but not in females. In the present study we confirmed that DCA pretreatment potentiates the CHCl 3-hepatotoxicity of both male and female rats. However, there was little evidence that DCA pretreatment significantly affected CHCl 3 disposition or increased CHCl 3 binding in vivo.