title: Nephrotoxicity of hexachloro-1:3-butadiene in the male Hanover Wistar rat; correlation of minimal histopathological changes with biomarkers of renal injury.
abstract: Hexachloro-1:3-butadiene (HCBD) causes damage specifically to the renal proximal tubule in rats. In the present study, injury to the nephron of male Hanover Wistar rats was characterized at 24 h following dosing with HCBD in the range 5-90 mg kg⁻¹ to determine the most sensitive biomarkers of damage, that is, the biomarkers demonstrating significant changes at the lowest dose of HCBD, using a range of measurements in serum and urine, renal histopathology, and renal and hepatic gene expression. Histologically, kidney degeneration was noted at doses as low as 10 mg kg⁻¹ HCBD. Significant changes in the hepatic and renal gene expression categories of xenobiotic metabolism and oxidative stress were observed at 5 mg kg⁻¹ HCBD, and in the kidney alone, evidence of inflammation at 90 mg kg⁻¹ HCBD. Increases in the urinary excretion of α-glutathione S-transferase (α-GST) and kidney injury molecule-1 (KIM-1) were seen at 10 mg kg⁻¹ HCBD, and increases in urinary excretion of albumin and total protein were evident at 15 mg kg⁻¹ HCBD. The most sensitive, noninvasive biomarkers of HCBD-induced renal toxicity in Hanover Wistar rats were urinary α-GST and KIM-1. Urinary albumin measurement is also recommended as, although it is not the most sensitive biomarker, together with α-GST, albumin showed the largest relative increase of all the biomarkers investigated, and the protein is easily measured.
authors: Clinical Pathology, GlaxoSmithKline Research and Development, Park Road, Ware, Hertfordshire SG12 0DP, UK. aubrey.2.swain@gsk.com
authors: Aubrey
authors: A
authors: Swain
authors: John
authors: J
authors: Turton
authors: Cheryl
authors: C
authors: Scudamore
authors: David
authors: D
authors: Maguire
authors: Ines
authors: I
authors: Pereira
authors: Sofia
authors: S
authors: Freitas
authors: Rosemary
authors: R
authors: Smyth
authors: Michael
authors: M
authors: Munday
authors: Clare
authors: C
authors: Stamp
authors: Mitul
authors: M
authors: Gandhi
authors: Surjit
authors: S
authors: Sondh
authors: Holly
authors: H
authors: Ashall
authors: Ian
authors: I
authors: Francis
authors: Jennifer
authors: J
authors: Woodfine
authors: John
authors: J
authors: Bowles
authors: Malcolm
authors: M
authors: York
mesh_terms: D000419:Albuminuria / Q000097:blood / Q000175:diagnosis / Q000652:urine; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002070:Butadienes / Q000633:toxicity*; D015815:Cell Adhesion Molecules / Q000097:blood / Q000235:genetics / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005659:Fungicides, Industrial / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D005982:Glutathione Transferase / Q000097:blood / Q000652:urine; D007274:Injections, Intraperitoneal; D007527:Isoenzymes / Q000097:blood / Q000652:urine; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000648:ultrastructure; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D002070:Butadienes; D015815:Cell Adhesion Molecules; D005659:Fungicides, Industrial; D005982:Glutathione Transferase; D007527:Isoenzymes; C110936:Havcr1 protein, rat; C001335:hexachlorobutadiene; C119995:glutathione S-transferase alpha