Chemical modification of acute hepatotoxicity of vinyl chloride monomer in rats

Abstract

Six-hour inhalation exposure of male rats to vinyl chloride monomer (VCM) was hepatotoxic as measured by elevated serum alanine-a-ketoglutarate transaminase (AKT) when the rats were pretreated with either sodium phenobarbital (0.1% in the drinking water, 7 days) or Aroclor 1254 (pretreatment doses given by gavage; 100, 200, or 300 μmol/kg/day for 3 days). Following Aroclor 1254 pretreatment and VCM exposure, serum AKT elevation was proportional to Aroclor 1254 dose as well as VCM concentration (range 12,500–50,000 ppm). In phenobarbital-pretreated rats, fasting, but not diethyl maleate, significantly potentiated VCM injury; SKF-525A (75 mg/kg, ip) given 30 min prior to exposure prevented liver injury produced by VCM. Both Aroclor 1254 and phenobarbital pretreatment increased in vitro liver hexobarbital oxidase activity in unexposed animals. Exposure to VCM caused hexobarbital oxidase activity to decrease in livers from both nonpretreated and pretreated rats. The decreases in activity did not correlate with injury as measured by serum AKT. Ethyl alcohol (3.33 ml/kg) given by gavage 30 min prior to VCM exposure in phenobarbital-pretreated rats was associated with a nonsignificant serum AKT increase when compared to controls not given ethanol. A larger dose of ethanol (5 ml/kg, po) given to Aroclor 1254-pretreated rats prior to VCM did not increase the serum AKT elevation compared to controls. Four doses of ethanol (5 ml/kg, po) given to phenobarbital-pretreated rats at 48, 42, 24, and 16 hr before VCM exposure did not potentiate the increase in serum AKT caused by VCM. Disulfiram (200 mg/kg, ip, or 1000 mg/kg, po) given prior to VCM exposure in Aroclor-pretreated rats produced a significant potentiation of VCM toxicity. The data suggest: first, that VCM is activated to a toxic intermediate and this activation is inducible; second, while ethyl alcohol per se does not appear to play a primary or modifying role in acute VCM hepatotoxicity, inhibitors of ethanol metabolism modify the toxicity of VCM.