TY - JOUR
T1 - In vivo and in vitro nephrotoxicity of the cysteine conjugate of hexachlorobutadiene
AU - Jaffe, Deborah R.
AU - Hassall, Christopher D.
AU - Brendel, Klaus
AU - Gandolfi, A. Jay
N1 - Funding Information:
Hexachlorobutadiene (HCBD) is a by-product in the synthesis of perchlorethylene and trichloroethylene and a prominent environmental A preliminary report of this study appeared in abstract form in The Pharmacologist, vol. 24, 107, 1981. C. D. H. is a Procter and Gamble Pre-Doctoral Fellow. Supported inpart by National Institutes of Health grant Am 16715. Requests for reprints should be sent to Deborah R. Jaffe, Department of Molecular Biology, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona 85724.
PY - 1983
Y1 - 1983
N2 - Hexachlorobutadiene (HCBD), a renal toxin and carcinogen, is thought to require bioactivation to exert toxicity. The chemically synthesized cysteine conjugate of structurally simitar haiogenated hydrocarbons, trichloroethylene, chlorotrifluoro- ethylene, and chlorodifluoroethylene, have been shown to be nephrotoxic. Hence the cysteine conjugate of HCBD, S-pentachlorobuta-l,3-dienyl cysteine (PCBC), was assessed for potential nephrotoxicity. Active acid and base transport in isolated rabbit renal tubules was used to screen nephrotoxicity. A dose-dependent decrease in acid and base transport was observed after incubation with PCBC. At 10-5 M PCBC transport was similar to that in controls, while at 1O-3 M PCBC completely inhibited active transport, in addition, in vivo exposure of Swiss-Webster male mice caused dose-dependent damage in the pars recta region of the proximal tubules (5-25 mgjkg ip). Genotoxicity in renal tissue was studied by using alkaline elution to detect DNA singlestrand breaks and total cross-links. No DNA single-strand breaks were observed in isolated rabbit renal tubules after exposure to 10-3 to 10-5 M PCBC. However, at I0-3 M PCBC there was some evidence of DNA cross-links. Therefore if cysteine conjugates of HCBD are formed in vivo, they could account for the toxicity observed with exposure to HCBD.
AB - Hexachlorobutadiene (HCBD), a renal toxin and carcinogen, is thought to require bioactivation to exert toxicity. The chemically synthesized cysteine conjugate of structurally simitar haiogenated hydrocarbons, trichloroethylene, chlorotrifluoro- ethylene, and chlorodifluoroethylene, have been shown to be nephrotoxic. Hence the cysteine conjugate of HCBD, S-pentachlorobuta-l,3-dienyl cysteine (PCBC), was assessed for potential nephrotoxicity. Active acid and base transport in isolated rabbit renal tubules was used to screen nephrotoxicity. A dose-dependent decrease in acid and base transport was observed after incubation with PCBC. At 10-5 M PCBC transport was similar to that in controls, while at 1O-3 M PCBC completely inhibited active transport, in addition, in vivo exposure of Swiss-Webster male mice caused dose-dependent damage in the pars recta region of the proximal tubules (5-25 mgjkg ip). Genotoxicity in renal tissue was studied by using alkaline elution to detect DNA singlestrand breaks and total cross-links. No DNA single-strand breaks were observed in isolated rabbit renal tubules after exposure to 10-3 to 10-5 M PCBC. However, at I0-3 M PCBC there was some evidence of DNA cross-links. Therefore if cysteine conjugates of HCBD are formed in vivo, they could account for the toxicity observed with exposure to HCBD.
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U2 - 10.1080/15287398309530389
DO - 10.1080/15287398309530389
M3 - Article
C2 - 6620416
AN - SCOPUS:0020609675
SN - 0098-4108
VL - 11
SP - 857
EP - 867
JO - Journal of Toxicology and Environmental Health
JF - Journal of Toxicology and Environmental Health
IS - 4-6
ER -