The metabolism and disposition of hexachloro-1:3-butadiene in the rat and its relevance to nephrotoxicity

Nash, John A.; King, Laurence J.; Lock, Edward A.; Green, Trevor

doi:10.1016/0041-008x(84)90061-9

Cited by 195 publications

(42 citation statements)

References 51 publications

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“…Giemsa. x 40. creted in the bile as an HCBD-glutathione (GSH) conjugate (52), and transported to the kidney where it is converted to a cysteine conjugate by the enzymes GGT and cysteinyl glycinase, which are concentrated to a great extent in the pars recta of the proximal tubules (13,14,38,49,61 (39). Although other segments are known to be affected (40), metabolic activation due to the presence of 0-lease in the S3 segment (pars recta) is thought to be the reason for its vulnerability (39,44).…”

Section: Histochemistrymentioning

confidence: 99%

Enhanced Hexachloro-1:3-butadiene Nephrotoxicity in Rats with a Preexisting Adriamycin-Induced Nephrotic Syndrome

Kirby

Bach

1995

Toxicol Pathol

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Renal damage was assessed by histopathology and urinalysis in male Wistar rats treated with either hexachloro-1:3-butadiene (HCBD; a single 170-mg/kg ip dose that caused proximal tubule necrosis), adriamycin (ADR; a single 5-mg/kg ip dose that caused minimal glomerular changes up to 35 days), or HCBD given 2 wk after ADR and compared with age-matched control rats for 21 days. Urinalysis values in ADRtreated rats showed minimal renal changes. HCBD significantly elevated urine volume (10-fold), protein (5-fold), glucose (175-fold), and brush border enzymes (10-600-fold), indicating severe proximal tubular damage, but most parameters returned to pretreatment levels 6 days after treatment. In ADR-pretreated rats subsequently given HCBD, both the urinary alkaline phosphatase and the ratio of kidney : body weight were significantly higher for longer periods. Histopathology demonstrated that the HCBD-induced proximal tubular lesion was confined to the outer stripe of the outer medulla. Advanced regeneration and repair was evident 21 days after HCBD treatment. In the ADR-pretreated rats the HCBD-induced lesion was more severe and affected the entire cortex (24).Statistics. Statistically significant differences between groups were determined by 2-tailed Students' t-test, with p < 0.05 considered to be statistically significant. RESULTS UrinanalysisThere were no significant differences in the urinary parameters in the control and ADR groups ( (Fig. 1 a). Tubules were dilated and filled with homogenous eosinophilic material and necrotic epithelial cells. Signs of regeneration and restitution (i.e., tubular re-epithelialization and loss of tubular casts and debris) were evident by day 7 and complete 21 days after treatment (Fig. 1 b).Histologically, animals in the ADR/HCBD group showed much more extensive renal damage (Fig. 2a) when compared to those treated with HCBD alone (see Fig. 1 a). Extensive tubular damage was present throughout the entire cortex 2 days after HCBD treatment, and tubules were dilated and filled with homogeneous proteinaceous material. Sloughed necrotic calcified epithelial cells were observed in tubular lumens and casts extended deep into the medulla (Fig. 2b). Extensive calcification was evident by day 7 (which was not seen in the HCBD only group) and by day 21, regeneration, although apparent, was less advanced and marked tubular calcification was still evident (Fig. 2c). Table 2 summarizes the differences between the ADR/HCBD group and HCBD alone. HistochemistryControl kidneys demonstrated normal GGT staining of the tubular epithelium of the outer stripe of the outer medulla (Fig. 3a). ADR caused no changes in this staining pattern. GGT staining in the outer stripe of the outer medulla was diminished 24 hr after HCBD treatment, was barely evident by day 3 (Fig. 3b) HCBD is a useful model toxin for damaging the proximal tubule. It is metabolized in the liver, ex-

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Section: Histochemistrymentioning

confidence: 99%

Enhanced Hexachloro-1:3-butadiene Nephrotoxicity in Rats with a Preexisting Adriamycin-Induced Nephrotic Syndrome

Kirby

Bach

1995

Toxicol Pathol

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“…The reactive fragments generated from nephrotoxic cysteine 5-conjugates apparently destroy renal epithelial cells by a combination of covalent binding to macromolecules, depletion of nonprotein thiols, and lipid peroxidation [7]. The S3 region of the kidney is especially vulnerable to the action of toxic cysteine 5-conjugates [8]. Within kid ney cells, the mitochondria are damaged [5,7].…”

Section: Introductionmentioning

confidence: 99%

Inactivation of Brain and Kidney Aspartate Aminotransferases by S-(1,2-Dichlorovinyl)-L-Cysteine and by S-(1,1,2,2-Tetrafluoroethyl)-L-Cysteine

Kato

Asano²,

Cooper³

1996

Dev Neurosci

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Long-term exposure to trichloroethylene can cause kidney cancer in experimental animals and humans. In addition, dichloroacetylene (a breakdown product of trichloroethylene) is nephrotoxic and neurotoxic. Both trichloroethylene and dichloroacetylene are metabolized in part to the corresponding cysteine S-conjugate (i.e. S-(1,2-dichlorovinyl)-L-cysteine) which is toxic. Cysteine S-conjugate β-lyases convert S-(1,2-dichlorovinyl)-L-cysteine to pyruvate, ammonia and a reactive fragment that adds to macromolecules, depletes cellular thiols and causes lipid peroxidation. We now show that S-(1,2-dichlorovinyl)-L-cysteine and another nephrotoxic cysteine S-conjugate, S-(1,1,2,2-tetrafluoroethyl)-L-cysteine, inactivate purified cytosolic aspartate aminotransferase and purified alanine aminotransferase. These cysteine S-conjugates also inactivate aspartate aminotransferase in cytosolic and mitochondrial fractions of rat brain and kidney. The present results suggest that some halogenated xenobiotics may be toxic in part through their conversion to the corresponding cysteine S-conjugate which inactivates key pyridoxal 5’-phosphate-containing enzymes.

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“…While the mechanism behind this difference is beyond the scope of the present study, we can speculate on the metabolic mechanism behind 2,4-DCNB induced renal toxicity. Nash et al (1984) and Dekant et al (1986) studied the toxic effects of chlorinated aliphatic compounds. Nash et al (1984) reported that nephrotoxic and nephrocarcinogenic effects were induced by hexachlorobutadiene (HCBD) and that the effects were caused by the glutathione conjugate of HCBD being degraded to its equivalent cysteine conjugate which was subsequentcaused localized kidney damage.…”

Section: Resultsmentioning

confidence: 99%

“…Nash et al (1984) and Dekant et al (1986) studied the toxic effects of chlorinated aliphatic compounds. Nash et al (1984) reported that nephrotoxic and nephrocarcinogenic effects were induced by hexachlorobutadiene (HCBD) and that the effects were caused by the glutathione conjugate of HCBD being degraded to its equivalent cysteine conjugate which was subsequentcaused localized kidney damage. Similarly, Dekant et al (1986) reported that trichloroethylene was metabolized to the N-acetylcysteine conjugate 4-acetyl-S-(1,2-dichlorovinyl)-L induce its nephrotoxic effects.…”

Section: Resultsmentioning

confidence: 99%

Identification of an N-acetylcysteine conjugate in the urine after oral administration of 2,4-dichloro-1-nitrobenzene to rats

et al. 2009

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The metabolism and disposition of hexachloro-1:3-butadiene in the rat and its relevance to nephrotoxicity

Cited by 195 publications

References 51 publications

Enhanced Hexachloro-1:3-butadiene Nephrotoxicity in Rats with a Preexisting Adriamycin-Induced Nephrotic Syndrome

Enhanced Hexachloro-1:3-butadiene Nephrotoxicity in Rats with a Preexisting Adriamycin-Induced Nephrotic Syndrome

Inactivation of Brain and Kidney Aspartate Aminotransferases by <i>S</i>-(1,2-Dichlorovinyl)-<i>L</i>-Cysteine and by <i>S</i>-(1,1,2,2-Tetrafluoroethyl)-<i>L</i>-Cysteine

Identification of an N-acetylcysteine conjugate in the urine after oral administration of 2,4-dichloro-1-nitrobenzene to rats

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