University of Surrey

Test tubes in the lab Research in the ATI Dance Research

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

Nash, John Anthony. (1985) The metabolism and disposition of hexachloro-1:3-butadiene in the rat and its relevance to nephrotoxicity. Doctoral thesis, University of Surrey (United Kingdom)..

[img]
Preview
Text
10804302.pdf
Available under License Creative Commons Attribution Non-commercial Share Alike.

Download (6MB) | Preview

Abstract

Following oral administration of a nephrotoxic dose (200mg/kg) of hexachloro-1:3-butadiene (HCBD) to male rats, bile was the principal route of excretion, 17-20% of the dose being eliminated on each of the first two days. Faecal excretion over this period was less than 5% of the dose per day, suggesting enterohepatic recirculation of biliary metabolites. Urinary excretion was small, not exceeding 3.5% of the dose during any 24hr period. Incubation of HCBD with rat liver microsomes in vitro gave a product which was chromatographically (TLC) similar to the major biliary metabolite of HCBD. The in vitro and major biliary metabolite were identified as S-(1,1,2,3,4-pentachloro-1,3-butadienyl)glutathione which demonstrated a direct conjugation reaction without prior oxidation. The cysteinylglycine conjugate of HCBD was also found in bile. Evidence has been obtained to show that biliary metabolites of HCBD are reabsorbed and excreted via the kidneys. Whole body autoradiography demonstrated a high concentration of radioactivity in the outer medulla of the kidney on dosing [[14]C]-HCBD. The glutathione conjugate, its mercapturic acid derivative and bile containing HCBD metabolites are all nephrotoxic when dosed orally to rats. In common with HCBD, these metabolites cause localised damage to the kidney with minimal effects in the liver. Rats fitted with a biliary cannula were completely protected from kidney damage when dosed with HCBD, demonstrating that hepatic metabolites are solely responsible for the nephrotoxicity of this compound. It is proposed that the hepatic glutathione conjugate of HCBD was degraded to its equivalent cysteine conjugate which was cleaved by the renal cytosolic enzyme B-lyase to give a toxic thiol which caused localised kidney damage. A urinary sulphenic acid metabolite of HCBD has been identified which is consistent with this hypothesis. The mode of activation of HCBD conjugates in the kidney is believed to be analogous to that proposed for S-(1,2-dichloro-vinyl)-L-cysteine.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors :
NameEmailORCID
Nash, John Anthony.
Date : 1985
Contributors :
ContributionNameEmailORCID
http://www.loc.gov/loc.terms/relators/THS
Additional Information : Thesis (M.Phil.)--University of Surrey (United Kingdom), 1985.
Depositing User : EPrints Services
Date Deposited : 22 Jun 2018 14:25
Last Modified : 06 Nov 2018 16:53
URI: http://epubs.surrey.ac.uk/id/eprint/847841

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year


Information about this web site

© The University of Surrey, Guildford, Surrey, GU2 7XH, United Kingdom.
+44 (0)1483 300800