BONE-MARROW AND RENAL INJURY ASSOCIATED WITH HALOALKENE CYSTEINE CONJUGATES IN CALVES

Almost 40 years ago, it was reported that cattle-feed which had been e xtracted with hot trichloroethylene and then fed to calves produced re nal injury and a fatal aplastic anaemia. The toxic factor was subseque ntly identified as S-(1,2-dichlorovinyl)-L-cysteine (DCVC). These orig inal findings have been confirmed, a single intravenous dose of DCVC a t 4 mg/kg, or 0.4 mg/kg intravenously per day administered for 10 days to calves produced aplastic anaemia, and renal injury after a single dose of 4 mg/kg. The toxicity to calves of a number of other haloalken e cysteine conjugates has been examined to ascertain whether, like DCV C, they produce bone marrow and renal injury. Intravenous administrati on of the N-acetyl cysteine conjugate of DCVC produced renal but not b one marrow injury at a molar equivalent dose to DCVC, indicating that the calf can deacetylate the mercapturic acid and further that suffici ent chemical had reached the kidney to be a substrate for the enzyme c ysteine conjugate beta-lyase. However, intravenous administration of t he alpha-methyl analogue of DCVC, which cannot undergo metabolism via the enzyme cysteine conjugate beta-lyase, was without toxicity at dose s about five-fold higher than DCVC. These latter findings provide stro ng evidence that metabolism of DCVC via the enzyme beta-lyase is neces sary for bone marrow and renal injury to occur. The cysteine conjugate s of perchloroethylene and hexachloro-1,3-butadiene(HCBD) when given i ntravenously to calves at molar equivalent doses to DCVC, or above, di d not produce either bone marrow or renal injury. In contrast, intrave nous administration of the cysteine conjugate of tetrafluoroethylene ( TFEC) produced severe renal tubular injury in calves without affecting the bone marrow. In vitro studies with these haloalkene cysteine conj ugates showed, like DCVC, that they were good substrates for calf rena l cysteine conjugate beta-lyase and toxic to renal cells as judged by their ability to reduce organic anion and cation transport by slices o f calf renal cortex and inhibit the renal enzyme glutathione reductase . Calves were also dosed either orally or intravenously with HCBD to a ssess its toxicity. HCBD at higher molar equivalent doses than DCVC pr oduced mid-zonal necrosis in the liver, renal tubular necrosis but no bone marrow injury in calves. The key findings emerging from these stu dies are (1) that none of the other cysteine conjugates, at molar equi valent doses to DCVC and above, produce bone marrow injury in calves, (2) TFEC produced only renal injury, suggesting that sufficient of the other conjugates had not reached the kidney for metabolism by beta-ly ase to produce cytotoxicity and (3) that HCBD itself is more toxic tha n its cysteine or mercapturic acid conjugate, suggesting that pharmaco kinetics and disposition are important factors in determining the toxi city of these conjugates to calves. Further studies are needed to unde rstand the basis for the selective toxicity of DCVC to the bone marrow of calves.