Medical management of inflammatory bowel disease: old and new perspectives

Nash, Carla; Sutherland, Lloyd R.

doi:10.1097/00001574-200107000-00007

Cited by 9 publications

(7 citation statements)

References 33 publications

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“…Azathioprine (aza) is widely used as an immunosuppressant in the treatment of antiimmune diseases (Nash and Sutherland, 2001), as well as in organ transplantation (Ponticelli et al, 1999), but 10-30% of patients cannot tolerate its adverse effects (Ahsen et al, 2005). Hepatotoxicity, one of the main side effects of azathioprine in clinical use, is evidenced in vivo by dosedependent transaminase elevations and centrilobular hepatocyte damage (Starzl et al, 1965;Haxhe et al, 1967).…”

Section: Introductionmentioning

confidence: 99%

Azathioprine hepatotoxicity and the protective effect of liquorice and glycyrrhizic acid

Shen

Yin

et al. 2006

Phytotherapy Research

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This study aimed to evaluate the responses of human hepatocytes to azathioprine hepatotoxicity in comparison with the well-studied azathioprine hepatotoxicity in rat hepatocytes and the effects of protective agents to suppress azathioprine hepatotoxicity. Azathioprine presented its hepatotoxicity at clinically relevant concentrations (lower than 10 microm) in primary rat hepatocytes after 48 h of treatment as shown by a severe decrease in cell viability as well as intracellular GSH depletion. However, primary human hepatocytes exhibited only significant intracellular GSH depletion after treatment with azathioprine at these clinically relevant concentrations, while a reduction in cell viability by 29% was only evidenced after 48 h of treatment with azathioprine at the high concentration of 50 microm. In addition, a monolayer culture of primary rat hepatocytes was used as an in vitro model to examine the protective effects of antihepatotoxic drugs including glutathione (GSH), N-acetylcysteine (NAC, a GSH precursor), liquorice and glycyrrhizic acid (GA), a major bioactive component of liquorice, against hepatotoxicity of 1 microm azathioprine. It was found that both liquorice and GA showed substantial protection according to assays of cell viability and intracellular GSH, while neither GSH nor NAC had such a protective function. Similarly, GA protected human hepatocytes from intracellular GSH depletion on exposure to 1 microm azathioprine. These results implied that GA or liquorice could be considered as potent protection agents against azathioprine hepatotoxicity.

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Section: Introductionmentioning

confidence: 99%

Azathioprine hepatotoxicity and the protective effect of liquorice and glycyrrhizic acid

Shen

Yin

et al. 2006

Phytotherapy Research

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“…Azathioprine (Aza) is an immunosuppressant widely used in the treatment of autoimmune diseases (Nash and Sutherland, 2001) and in organ transplantation (Ponticelli et al, 1999). It has even been reported that 3.5% of 173 inflammatory bowel disease patients treated with Aza developed hepatitis as a consequence of treatment (Rietdijk et al, 2001).…”

mentioning

confidence: 99%

Azathioprine Acts upon Rat Hepatocyte Mitochondria and Stress-Activated Protein Kinases Leading to Necrosis: Protective Role of N-Acetyl-L-cysteine

Menor¹,

Fernández‐Moreno²,

Fueyo³

et al. 2004

J Pharmacol Exp Ther

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Azathioprine is an immunosuppressant drug widely used. Our purpose was to 1) determine whether its associated hepatotoxicity could be attributable to the induction of a necrotic or apoptotic effect in hepatocytes, and 2) elucidate the mechanism involved. To evaluate cellular responses to azathioprine, we used primary culture of isolated rat hepatocytes. Cell metabolic activity, reduced glutathione, cell proliferation, and lactate dehydrogenase release were assessed. Mitochondria were isolated from rat livers, and swelling and oxygen consumption were measured. Mitogen-activated protein kinase pathways and proteins implicated in cell death were analyzed. Azathioprine decreased the viability of hepatocytes and induced the following events: intracellular reduced glutathione (GSH) depletion, metabolic activity reduction, and lactate dehydrogenase release. However, the cell death was not accompanied by DNA laddering, procaspase-3 cleavage, and cytochrome c release.The negative effects of azathioprine on the viability of hepatocytes were prevented by cotreatment with N-acetyl-L-cysteine. In contrast, 6-mercaptopurine showed no effects on GSH content and metabolic activity. Azathioprine effect on hepatocytes was associated with swelling and increased oxygen consumption of intact isolated rat liver mitochondria. Both effects were cyclosporine A-sensitive, suggesting an involvement of the mitochondrial permeability transition pore in the response to azathioprine. In addition, the drug's effects on hepatocyte viability were partially abrogated by c-Jun N-terminal kinase and p38 kinase inhibitors. In conclusion, our findings suggest that azathioprine effects correlate to mitochondrial dysfunction and activation of stress-activated protein kinase pathways leading to necrotic cell death. These negative effects of the drug could be prevented by coincubation with N-acetyl-L-cysteine.

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“…2002). Many patients with IBD will relapse without treatment (Nash & Sutherland 2001) but Aza and 6‐MP are proven to be valuable in maintaining remission of the disease over a longer period (Hawthorne 1992, Fraser et al. 2002).…”

Section: Literature Reviewmentioning

confidence: 99%

“…2002). Additionally, they can prevent, or at least delay, surgery (Hanauer 1996, Nash & Sutherland 2001).…”

Section: Literature Reviewmentioning

confidence: 99%

See 1 more Smart Citation

A triangulation study of the clinician and patient experiences of the use of the immunosuppressant drugs azathioprine and 6‐mercaptopurine for the management of inflammatory bowel disease

Holbrook

2007

Journal of Clinical Nursing

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Medical management of inflammatory bowel disease: old and new perspectives

Cited by 9 publications

References 33 publications

Azathioprine hepatotoxicity and the protective effect of liquorice and glycyrrhizic acid

Azathioprine hepatotoxicity and the protective effect of liquorice and glycyrrhizic acid

Azathioprine Acts upon Rat Hepatocyte Mitochondria and Stress-Activated Protein Kinases Leading to Necrosis: Protective Role of N-Acetyl-L-cysteine

A triangulation study of the clinician and patient experiences of the use of the immunosuppressant drugs azathioprine and 6‐mercaptopurine for the management of inflammatory bowel disease

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