ToxSci Advance Access published online on May 28, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg125
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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1 Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609
* To whom correspondence should be addressed. E-mail: mkanz{at}utmb.edu.
Methylenedianiline (DAPM) initially injures epithelial cells of major bile ducts followed by cholestasis, cholangitis and hepatocellular damage. This pattern of biliary injury resembles that produced by
© 2003 Society of Toxicology
Systems Toxicology
Glutathione Depletion Exacerbates Methylenedianiline Toxicity to Biliary Epithelial Cells and Hepatocytes in Rats
2 Department of Pharmacology, Louisiana State University Health Science Center-Shreveport, Shreveport, LA 71130-3932
Abstract 
-naphthylisothiocyanate (ANIT), a classic bile duct toxicant. Our goal was to determine whether prior depletion of hepatic total glutathione (GSx), a condition reported to protect against biliary tract injury by ANIT, would also protect against DAPM-induced bile duct injury. A new protocol for extensive, sustained depletion of GSx was established. We found that administration of 1-bromoheptane followed 1 h later by buthionine sulfoximine resulted in an 
96% depletion of hepatic GSx that persisted through 6 h without biochemical or morphological signs of hepatic injury. Treatment of rats with a minimally hepatotoxic dose of DAPM (without GSx depletion) produced injury at 6 h similar to previous studies: moderate oncosis of biliary epithelial cells (BEC), mild edema of portal triads, and increases in glutathione S-transferase activities without alterations in hepatic GSx/GSSG, CoASH/CoASSG or TBARS. In contrast, DAPM treatment of GSx-depleted rats produced severe oncosis of BEC, marked inflammatory and edematous alterations to portal tracts, and oncosis/apoptosis in scattered hepatocytes. The observed acceleration and enhancement of DAPM-induced liver injury by GSx depletion was associated with a concurrent 7-fold increase in hepatic CoASSG and a 4-fold decrease in the ratio of CoASH to CoASSG, compounds presumably localized to mitochondria and a purported index of mitochondrial thiol/disulfide status. These results indicate that: 1) GSx depletion exacerbates BEC and hepatocellular injury induced by DAPM, and 2) the mechanism by which DAPM causes liver injury is likely different from that of the classic bile duct toxicant, ANIT.
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