Ea. Lock et al., BONE-MARROW AND RENAL INJURY ASSOCIATED WITH HALOALKENE CYSTEINE CONJUGATES IN CALVES, Archives of toxicology, 70(10), 1996, pp. 607-619
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.