Biochemical Mechanisms of Toxicity of Orthochlorophenol.

Abstract

Orthochlorophenol represents a significant and moderately persistent contaminant in water in localized areas. This research examines the in vivo and in vitro metabolism of orthochlorophenol as it relates to the toxicity of this compound. After oral administration at 225 mg/kg to male Sprague-Dawley rats, orthochlorophenol was recovered in the urine in free form, as the glucuronide, and as glucuronide and sulfate conjugates of 2-chlorohydroquinone. When rats were pretreated with B-naphthoflavone or Arochlor 1254, the distribution of recovered metabolites in the urine reflected an increased formation of 2-chlorohydroquinone. No significant renal or hepatotoxicity was observed at this dose level. The in vitro metabolism of orthochlorophenol by liver microsomes produced 2-chlorohydroquinone as the major oxidation product. When radiolabeled orthochlorophenol was incubated with hepatic microsomes, covalent binding of radioactivity was observed. Binding of radioactivity could be decreased by reduced glutathione or L-cysteine. Orthochlorophenol was administered orally (300 mg/kg) to Gunn rats. These rats are deficient in the EDP-glucuronyl transferase pathway. After 24 hours orthochlorophenol was recovered in free form, as the glucuronide and sulfate, and as the sulfate conjugate of 2-chlorohydroquinone. The formation of 2-chlorohydroquinone in Gunn rats was 8-9 times greater than Sprague-Dawley rats. Centrilobular hepatic necrosis was observed in 50% and renal necrosis in 75% of the experimental animals. When radiolabeled orthochlorophenol was administered to rats, the binding of radioactivity to livers and kidneys of Gunn rats was 3-4 times greater than that in Sprague-Dawley rats. In the Gunn rats orthochlorophenol elicited hepatic and renal pathologic changes. The in vivo and in vitro data strongly suggest that orthochlorophenol is a substrate for the P-450 system. The binding data imply that orthochlorophenol is metabolized to an intermediate capable of binding to microsomal proteins. The in vivo data from the Gunn rats suggest that when the activity of the EDP-glucuronyl transferase pathway is diminished, orthochlorophenol may be increasingly oxidized via the P-450 pathway with concomitant increases in macromolecular binding and pathology.