Hepatotoxic effect of cyclosporin A in the mitochondrial respiratory chain

Rodriguez, Lilia; Araujo, Carmen Rosa; Posleman, Sara Emilia; Rey, María del Rosario

doi:10.1002/jat.1192

Cited by 6 publications

(5 citation statements)

References 22 publications

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“…GLDH and OCT are mitochondrial enzymes. An increased plasma activity of these enzymes reflects structural damage to the mitochondria and cell membrane, leading to the leakage of these enzymes into the plasma [111,112]. OCT is particularly expressed in the liver [111].…”

Section: The In Vitro Assaysmentioning

confidence: 99%

Drug‐induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies

Labbe

Pessayre

Fromenty

2008

Fundamemntal Clinical Pharma

274

254

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Mitochondrial dysfunction is a major mechanism whereby drugs can induce liver injury and other serious side effects such as lactic acidosis and rhabdomyolysis in some patients. By severely altering mitochondrial function in the liver, drugs can induce microvesicular steatosis, a potentially severe lesion that can be associated with profound hypoglycaemia and encephalopathy. They can also trigger hepatic necrosis and/or apoptosis, causing cytolytic hepatitis, which can evolve into liver failure. Milder mitochondrial dysfunction, sometimes combined with an inhibition of triglyceride egress from the liver, can induce macrovacuolar steatosis, a benign lesion in the short term. However, in the long term this lesion can evolve in some individuals towards steatohepatitis, which itself can progress to extensive fibrosis and cirrhosis. As liver injury caused by mitochondrial dysfunction can induce the premature end of clinical trials, or drug withdrawal after marketing, it should be detected during the preclinical safety studies. Several in vitro and in vivo investigations can be performed to determine if newly developed drugs disturb mitochondrial fatty acid oxidation (FAO) and the oxidative phosphorylation (OXPHOS) process, deplete hepatic mitochondrial DNA (mtDNA), or trigger the opening of the mitochondrial permeability transition (MPT) pore. As drugs can be deleterious for hepatic mitochondria in some individuals but not in others, it may also be important to use novel animal models with underlying mitochondrial and/or metabolic abnormalities. This could help us to better predict idiosyncratic liver injury caused by drug-induced mitochondrial dysfunction.

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Section: The In Vitro Assaysmentioning

confidence: 99%

Drug‐induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies

Labbe

Pessayre

Fromenty

2008

Fundamemntal Clinical Pharma

274

254

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“…CYA prevents mitochondrially mediated apoptosis by blocking the permeability transition pore, 32 but may inhibit mitochondrial respiratory chain enzymes. 33 Similarly, tacrolimus prevents apoptosis 34 but can also act as a mitochondrial toxin. 35 Despite its potentially toxic effects on mitochondria, CYA was well tolerated by 4 of 9 MNGIE patients without any obvious exacerbation of the neuropathy or the metabolic status by strict monitoring and maintenance of plasma levels of CYA or tacrolimus within the therapeutic range.…”

Section: Consensus Proposalmentioning

confidence: 99%

Allogeneic hematopoietic SCT as treatment option for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a consensus conference proposal for a standardized approach

Halter

Schüpbach

Casali

et al. 2010

Bone Marrow Transplant

106

139

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Allogeneic hematopoietic SCT (HSCT) has been proposed as a treatment for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). HSCT has been performed in nine patients using different protocols with varying success. Based on this preliminary experience, participants of the first consensus conference propose a common approach to allogeneic HSCT in MNGIE. Standardization of the transplant protocol and the clinical and biochemical assessments will allow evaluation of the safety and efficacy of HSCT as well as optimization of therapy for patients with MNGIE.

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“…In our work, we found that GGT u is an early marker of proximal tubular cell injury in cyclosporin A-induced nephrotoxicity (De la Cruz Rodríguez et al, 1996Rodríguez et al, , 2007. That is why we considered enzymuria, GGT u and NAG u , as early and sensitive markers of nephrotoxicity.…”

Section: Discussionmentioning

confidence: 70%

Attenuation of gentamicin‐induced nephrotoxicity: trimetazidine versus N‐acetyl cysteine

Rodriguez

Araujo

Posleman

et al. 2010

J of Applied Toxicology

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Gentamicin (G) is a highly nephrotoxic aminoglucoside. It was used to experimentally induce nephrotoxicity in male Wistar rats. To find a drug capable of protecting the nephron we assayed a cardioprotector (trimetazidine, TMZ) and a hepatoprotector (N-acetyl cysteine, NAC). The rats were divided into six groups (n = 8): (A) control without drugs; (B) treated with 50 mg kg(-1) per day (i.p.) of G for 7 days; (C) diet supplemented with 20 mg kg(-1) per day of TMZ for 7 days; (D) treated with 10 mg kg(-1) per day (i.p.) of NAC for 7 days; (E) pretreated for 7 days with 20 mg kg(-1) per day of TMZ and during the following 7 days with G + TMZ; (F) pretreated for 7 days with 10 mg kg(-1) per day (i.p.) of NAC and during the following 7 days with G + NAC. Urea and creatinine as well as the excretion of urinary gamma-glutamyl transpeptidase (GGT(u)) and urinary N-acetyl-glucosaminidase (NAG(u)) were determined and structural and ultrastructural studies were carried out. Group B was used as a G-induced nephrotoxicity control. Pretreatment with TMZ (E) showed a protector effect against induced nephrotoxicity, with no biochemical or functional changes nor alterations in histoarchitecture or ultrastructure. Pretreatment with NAC (F) showed no protector effect against G-induced nephrotoxicity since no statistically significant differences were found with respect to the control group with G. We conclude that G-induced nephrotoxicity is attenuated by the cytoprotective effect of TMZ. We may infer that TMZ inhibits the reabsorption and consequently the accumulation of G in the proximal tubule cell.

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Hepatotoxic effect of cyclosporin A in the mitochondrial respiratory chain

Cited by 6 publications

References 22 publications

Drug‐induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies

Drug‐induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies

Allogeneic hematopoietic SCT as treatment option for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a consensus conference proposal for a standardized approach

Attenuation of gentamicin‐induced nephrotoxicity: trimetazidine versus N‐acetyl cysteine

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