Effect in the rat of the interaction of dichloromaleic acid and carbon tetrachloride on renal and hepatic function.
Water purification generates a variety of chlorinated contaminants, one of which is dichloromaleic acid (DCMA). Exposure to this compound is likely to occur in combination with other drinking water pollutants, some of which are hepatotoxic. This study was designed to examine the interactive effects of carbon tetrachloride (CCl4), a known hepatotoxin, with DCMA on liver and kidney function in the Sprague-Dawley rat. Administration of a single dose of DCMA (200-400 mg/kg, ip) caused modest dose-dependent increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and plasma urea nitrogen, as well as a marked depletion of nonprotein sulfhydryls (NPSH) in the liver, but not the kidney, by 24 hr. Pretreatment with inducers (phenobarbital or 3-methylcholanthrene) or an inhibitor (SKF 525A) of cytochrome P-450 activity failed to alter the response observed with DCMA alone. Alterations in 24-hr urine volume, osmolality, and water consumption also were observed. DCMA-mediated changes in plasma urea nitrogen and NPSH were reduced in magnitude with coadministration of CCl4 (1 ml/kg, ip), while anticipated CCl4-induced increases in ALT and AST were reduced with coexposure to DCMA. Renal slice experiments indicated that DCMA-treated rats were less able to accumulate the organic anion p-aminohippurate (PAH), whereas DCMA had no effect on accumulation of the organic cation tetraethylammonium (TEA). The combination of CCl4 and DCMA produced only additive effects on organic ion accumulation. These results suggest hepatic interaction possibly related to the metabolism of CCl4 and DCMA, resulting in renal and hepatic toxicity diminished from that observed with exposure to either agent alone.
Christenson
W R
WR
Department of Pharmacology, College of Medicine, University of Nebraska Medical Center, Omaha 68105.
Davis
M E
ME
Berndt
W O
WO
D000818:Animals; D001806:Blood Urea Nitrogen; D002251:Carbon Tetrachloride / Q000633:toxicity*; D004326:Drinking / Q000187:drug effects; D005260:Female; D007668:Kidney / Q000187:drug effects*; D007677:Kidney Function Tests; D008099:Liver / Q000187:drug effects*; D008111:Liver Function Tests; D008297:Male; D008298:Maleates / Q000633:toxicity*; D008748:Methylcholanthrene / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014873:Water Pollutants / Q000633:toxicity*; D014874:Water Pollutants, Chemical / Q000633:toxicity*
D008298:Maleates; D014873:Water Pollutants; D014874:Water Pollutants, Chemical; C062588:dichloromaleic acid; D008748:Methylcholanthrene; D011335:Proadifen; D002251:Carbon Tetrachloride; D010634:Phenobarbital