Toxicity of low dose azathioprine and 6-mercaptopurine in rat hepatocytes. Roles of xanthine oxidase and mitochondrial injury

Tapner, Michael; Jones, Brett E.; Wu, Wan M; Farrell, Geoffrey C.

doi:10.1016/j.jhep.2003.11.024

Cited by 63 publications

(63 citation statements)

References 49 publications

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“…This is probably a general property of thiopurines. Consistent with our observations, both 6-MP and azathioprine have been shown to deplete reduced GSH in cultured human cells (23). ROS scavenging abrogated both 6-TG-mediated replication inhibition and FA pathway activation.…”

Section: Discussionsupporting

confidence: 91%

Oxidation-Mediated DNA Cross-Linking Contributes to the Toxicity of 6-Thioguanine in Human Cells

Brem

Karran

2012

Cancer Research

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The thiopurines azathioprine and 6-mercaptopurine have been extensively prescribed as immunosuppressant and anticancer agents for several decades. A third member of the thiopurine family, 6-thioguanine (6-TG), has been used less widely. Although known to be partly dependent on DNA mismatch repair (MMR), the cytotoxicity of 6-TG remains incompletely understood. Here, we describe a novel MMR-independent pathway of 6-TG toxicity. Cell killing depended on two properties of 6-TG: its incorporation into DNA and its ability to act as a source of reactive oxygen species (ROS). ROS targeted DNA 6-TG to generate potentially lethal replication-arresting DNA lesions including interstrand cross-links. These triggered processing by the Fanconi anemia and homologous recombination DNA repair pathways. Allopurinol protected against 6-TG toxicity by acting as a ROS scavenger and preventing DNA damage. Together, our findings provide mechanistic evidence to support the proposed use of thiopurines to treat HR-defective tumors and for the coadministration of 6-TG and allopurinol as an immunomodulation strategy in inflammatory disorders. Cancer Res; 72(18); 4787-95. Ó2012 AACR.

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Section: Discussionsupporting

confidence: 91%

Oxidation-Mediated DNA Cross-Linking Contributes to the Toxicity of 6-Thioguanine in Human Cells

Brem

Karran

2012

Cancer Research

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“…These observations are also consistent with observations in patients receiving PI: 1) The use of HIV PI such as NFV has reduced the incidence of pancreatitis in HIV-infected patients from as high as 14% in the pre-highly active antiretroviral therapy era to rates as low as 0.13, 0.35, and 0.85% since 1996 (8,31,33,40). 2) Nucleoside reverse transcriptase inhibitors such as didanosine (ddI), stauvidine (4dT), and agents such as azathioprine that are mitochondriotoxic cause pancreatitis (25,44). 3) NFV reduces incidence of pancreatitis caused by these agents (e.g., from 4.93% with ddI/d4T/efavirenz to 0% with NFV included, and from 6.25% in all regimens with ddI/d4T to 2.05% with NFV included in these) (32).…”

Section: Discussionmentioning

confidence: 99%

Nelfinavir/ritonavir reduces acinar injury but not inflammation during mouse caerulein pancreatitis

Singh

Bren

Algeciras‐Schimnich

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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There is no clinical treatment that reduces acinar injury during pancreatitis. Human immunodeficiency virus (HIV) protease inhibitors (PI), including nelfinavir (NFV) and ritonavir (RTV), may reduce the rate of pancreatitis in HIV-infected patients. Since permeability transition pore (PTPC)-mediated mitochondrial dysfunction occurs during pancreatitis, and we have shown that PI prevents PTPC opening, we studied its effects in a model of pancreatitis. The effect of NFV plus RTV (NFV/RTV) or vehicle on caerulein-induced pancreatitis in mice was compared by measuring changes in mitochondrial membrane potential in vitro and cytochrome c leakage in vivo. Histological and inflammatory makers were also compared. NFV/RTV improved DiOC6 retention in acini exposed to caerulein in vitro. In vivo NFV prevented cytosolic leakage of cytochrome c and reduced pancreatic acinar injury, active caspase-3 staining, TUNEL-positive acinar cells, and serum amylase ( P < 0.05). Conversely, trypsin activity, serum cytokine levels, and pancreatic and lung inflammation were unaffected. NFV/RTV reduces pancreatic injury and acinar cell death in experimental mouse caerulein-induced pancreatitis but does not impact inflammation.

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“…2 In addition, the thiolysis of azathioprine to 6-mercaptopurine consumes GSH and leads to a rapid depletion of this molecule in the rat liver, 33 and in murine sinusoidal endothelial cells and hepatocytes, 34 leading to cell death by a mechanism that involves oxidative stress and mitochondrial injury; this phenomenon might also occur in other tissues, such as bone marrow and pancreatic tissues. 35,36 Depletion of GSH in response to oxidative stress is more evident in cells with high GST activity compared with those with low or absent activity, 21,22 therefore increased GSH consumption during azathioprine treatment may occur in patients with functional GST-M1 genotypes and this could lead to an increase in oxidative stress and tissue damage. This might be another mechanism at work in the increased incidence of lymphopenia and pancreatitis in patients with a functional GST genotype.…”

Section: Discussionmentioning

confidence: 99%

Glutathione-S-transferase genotypes and the adverse effects of azathioprine in young patients with inflammatory bowel disease

Stocco

Martelossi

Barabino

et al. 2007

Inflammatory Bowel Diseases

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Toxicity of low dose azathioprine and 6-mercaptopurine in rat hepatocytes. Roles of xanthine oxidase and mitochondrial injury

Cited by 63 publications

References 49 publications

Oxidation-Mediated DNA Cross-Linking Contributes to the Toxicity of 6-Thioguanine in Human Cells

Oxidation-Mediated DNA Cross-Linking Contributes to the Toxicity of 6-Thioguanine in Human Cells

Nelfinavir/ritonavir reduces acinar injury but not inflammation during mouse caerulein pancreatitis

Glutathione-S-transferase genotypes and the adverse effects of azathioprine in young patients with inflammatory bowel disease

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