Dichloroacetic acid pretreatment of male and female rats increases chloroform-induced hepatotoxicity.
Dichloroacetic acid (DCA) and chloroform (CHCl3) are both major by-products of drinking water chlorination and DCA increases the hepatotoxicity of CHCl3. In this study, we further characterized this effect and investigated DCA-induced alterations of CHCl3 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 CHCl3 (3.12 or 9.35 mmol/kg). Hepatic damage was assessed 24 h after CHCl3 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 14CHCl3 at the same dosages. The disposition of 14C in various tissues and covalent binding of 14CHCl3-derivatives to liver proteins and lipids were determined 1 h later. CHCl3-induced hepatotoxicity was significantly more severe in DCA-pretreated groups. ALT and OCT were more markedly elevated in DCA + CHCl3 (3.12 mmol/kg) groups than NaCl +CHCl3 animals. Plasma bilirubin content was elevated only in DCA + CHCl3 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 CHCl3-hepatotoxicity of both male and female rats. However, there was little evidence that DCA pretreatment significantly affected CHCl3 disposition or increased CHCl3 binding in vivo.
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; D002725:Chloroform / Q000378:metabolism / Q000633:toxicity*; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors
D002725:Chloroform; D003999:Dichloroacetic Acid