1,1‐Dichloroethylene hepatotoxic1ty: Effect of altered thyroid function and evidence for the subcellular site of injury

Abstract

Male Sprague‐Dawley rats were exposed for 4 hr to 1,1‐dichloroethylene (1,1‐DCE) by inhalation following an 18 hr fast. They were killed at 6 hr. Under these circumstances, prior thyroidectomy caused a decrease in the severity of the injury as measured by elevation of serum alanine‐α‐ketoglutarate transaminase (AKT), while thyroxine pretreatment (50 \ig per rat sc for 7 days) enhanced the hepatotoxicity of 1,1‐DCE as measured by lethality and serum AKT elevation. Chemical thyroidectomy using either propylthiouracil (30 mg/kg po for 7 days) or methimazole (15 mg/kg po for 7 days) also provided a degree of protection. Thyroidectomy, surgical or chemical, was associated with an increase in hepatic glutathione concentration, while thyroxine decreased the hepatic concentration of this nucleophile. Livers from rats exposed to 1,1‐DCE were found to have decreased in vitro oxygen uptake when supplied with succinate and ADP. This form of injury preceded the elevation in serum AKT, which occurred at 4 hr. Subcellular fractionation of livers from fed or fasted rats exposed to air or 1,1‐DCE showed that the heavy and light mitochondrial fractions from fasted, exposed rats had the largest decrease in glutathione concentration relative to the other groups. 1,1‐DCE exposure was associated with decreased glutathione concentration, but subtractions from fasted rats generally had the largest decreases. Serum sorbitol dehydrogenase, a cytoplasmic marker, was positively correlated to changes in serum ornithine carbarnoyl transaminase, a mitochondrial marker, suggesting that mitochondrial damage may occur before or at the same time as cytoplasmic membrane rupture. These latter findings are consistent with previously reported histologic observations. Based on these data, a mechanism for 1,1‐DCE is proposed.