Toxicity of azathioprine and monocrotaline in murine sinusoidal endothelial cells and hepatocytes: The role of glutathione and relevance to hepatic venoocclusive disease

✍ Scribed by L D DeLeve; X Wang; J F Kuhlenkamp; N Kaplowitz

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 384 KB
• Volume: 23
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510230326

✦ Synopsis

The mechanisms leading to hepatic venoocclusive dis-

Little is known about the causal mechanisms of heease (HVOD) remain largely unknown. Azathioprine and patic venoocclusive disease (HVOD). There has been monocrotaline were studied as part of a series of studies speculation as to whether hepatocytes or endothelial looking at a variety of toxins that induce HVOD to find cells might be the initial target, 1-4 but with little evicommon features that might be of pathogenic signifidence to support any of the contentions. Biopsy and cance. In a previous study, dacarbazine showed selective autopsy material demonstrate damage to both hepatoin vitro toxicity to sinusoidal endothelial cells (SEC) cytes or sinusoidal endothelial cells (SEC) early on. 1,2 compared with hepatocytes and a key role for SEC gluta-However morphology does not allow continuous monithione (GSH) was demonstrated. Murine SEC and hepatoring of changes and does not provide information on tocytes were isolated and studied in culture. Azathiosublethal damage that might lead to other events. Thus prine and monocrotaline were found to be selectively more toxic to SEC than to hepatocytes. The relative re-it is currently unknown why a variety of insults lead sistance of hepatocytes to azathioprine was due to ento HVOD rather than to another manifestation of liver hanced GSH defense: hepatocytes exposed to azathiotoxicity.

prine maintained intracellular GSH levels better than

Our approach to HVOD has been to study a number SEC, particularly when supplemental GSH precursors of chemically diverse compounds to search for common were added, and hepatocyte resistance was completely characteristics in an in vitro model. The first compound overcome by depletion of intracellular GSH. In contrast, studied, dacarbazine, demonstrated selective toxicity monocrotaline toxicity in hepatocytes was largely unafto SEC rather than to hepatocytes. 5 These studies also fected by depletion of GSH, which suggests that selectivdemonstrated that glutathione (GSH) plays a major ity of monocrotaline for SEC may be attributable to difrole in dacarbazine detoxification in the SEC. Based ferences in metabolic activation. Both compounds are on these findings, we have postulated that SEC GSH detoxified by GSH in SEC, as demonstrated by enhanced toxicity in the presence of buthionine sulfoximine (BSO) status may be a major determinant of susceptibility to and attenuation of toxicity with exogenous GSH. SEC this toxicity. In the current study, the characteristics of GSH levels were more than 70% to 80% depleted by moazathioprine and monocrotaline were studied in vitro. nocrotaline and azathioprine, respectively, before cell Azathioprine has been linked to multiple different death. Azathioprine and monocrotaline are selectively liver lesions in patients on long-term immunosupprestoxic to SEC; the mechanism of toxicity in the SEC may sion after kidney or liver transplantation: HVOD, sinube caused by profound GSH depletion. (HEPATOLOGY soidal dilatation, sinusoidal fibrosis, peliosis hepatis, 1996;23:589-599.)

and nodular regenerative hyperplasia. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] It has been speculated that all of these lesions are related to sinusoidal endothelial damage or disruption of the hepatic microcirculation. 10,[21][22][23][24] Azathioprine is extensively me-Abbreviations: HVOD, hepatic venoocclusive disease; SEC, sinusoidal epithelial cells; GSH, glutathione; DMEM, Dulbecco's minimum essential me-tabolized in the small intestine and liver by GSH Sdium; MTT, [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; ANOVA, transferase to 6-mercaptopurine. [25][26][27] This reaction conanalysis of variance; SAAF, sulfur amino acid-free medium; BSO, buthionine sumes GSH and leads to profound and rapid GSH sulfoximine; LSD, least significant difference; BPAE, bovine pulmonary endodepletion in the rat liver. 28 thelial cells.