Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone

Julie, Neil L.; Julie, I. M.; Kende, Anikó; Wilson, Glenn L.

doi:10.1007/s00125-008-1133-6

Cited by 46 publications

(27 citation statements)

References 65 publications

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“…Cells exposed to rotenone showed a 14 ± twofold increase in apoptosis (P < 0.001, n = 5), as well as unlabeled cell death, suggesting necrosis. Troglitazone is an antidiabetic and anti-inflammatory drug that was removed from market due to severe drug-induced liver injury (21). Though troglitazone mechanism of action is still unclear, its metabolites were shown to block bile acid transporters BSEP and MRP2, leading to cholestasis, whereas the parent compound was shown to decrease mitochondrial membrane potential (22).…”

Section: Real-time Oxygen Measurement Shows Rapid Loss Of Mitochondrialmentioning

confidence: 99%

Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

Bavli

Prill

Tsur

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

250

292

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Microfluidic organ-on-a-chip technology aims to replace animal toxicity testing, but thus far has demonstrated few advantages over traditional methods. Mitochondrial dysfunction plays a critical role in the development of chemical and pharmaceutical toxicity, as well as pluripotency and disease processes. However, current methods to evaluate mitochondrial activity still rely on end-point assays, resulting in limited kinetic and prognostic information. Here, we present a liveron-chip device capable of maintaining human tissue for over a month in vitro under physiological conditions. Mitochondrial respiration was monitored in real time using two-frequency phase modulation of tissue-embedded phosphorescent microprobes. A computer-controlled microfluidic switchboard allowed contiguous electrochemical measurements of glucose and lactate, providing real-time analysis of minute shifts from oxidative phosphorylation to anaerobic glycolysis, an early indication of mitochondrial stress. We quantify the dynamics of cellular adaptation to mitochondrial damage and the resulting redistribution of ATP production during rotenone-induced mitochondrial dysfunction and troglitazone (Rezulin)-induced mitochondrial stress. We show troglitazone shifts metabolic fluxes at concentrations previously regarded as safe, suggesting a mechanism for its observed idiosyncratic effect. Our microfluidic platform reveals the dynamics and strategies of cellular adaptation to mitochondrial damage, a unique advantage of organ-on-chip technology.microfluidics | liver tissue engineering | toxicology | organ-on-a-chip

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Section: Real-time Oxygen Measurement Shows Rapid Loss Of Mitochondrialmentioning

confidence: 99%

Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

Bavli

Prill

Tsur

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

250

292

View full text Add to dashboard Cite

show abstract

“…The exact mechanisms of its toxic action remain somewhat enigmatic, but a consensus has emerged that that troglitazone are toxic to mitochondria (Masubuchi, 2006;Julie et al, 2008). In addition, troglitazone administration in rats leads to an acute reduction to bile flow and hence is cholestatic (Preininger et al, 1999).…”

Section: Role Of Bsep In Acquired Cholestasismentioning

confidence: 99%

Role of the bile salt export pump, BSEP, in acquired forms of cholestasis

Stieger

2009

Drug Metabolism Reviews

109

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“…Troglitazone is a drug, which was withdrawn from the market as a consequence of severe hepatotoxicity. The detailed mechanism of troglitazone toxicity remains somewhat elusive, but involvement of mitochondrial toxicity has emerged as an agreed concept (79,80). In rats, the main metabolite of troglitazone is troglitazone sulphate, which is eliminated into bile (81).…”

Section: Mechanisms Of Bsep Inhibitionmentioning

confidence: 99%

Role of Membrane Transport in Hepatotoxicity and Pathogenesis of Drug-Induced Cholestasis

Stieger

Kullak‐Ublick

2013

Drug-Induced Liver Disease

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Drug-induced liver injury is an important clinical entity, which can be grouped into cholestatic liver injury, hepatocellular liver injury, and mixed liver injury. Cholestatic liver injury is characterized by a reduction in bile flow and the retention within hepatocytes of cholephilic compounds such as bile salts that cause hepatotoxicity. Bile salts are taken up by hepatocytes in a largely sodium-dependent manner and to a lesser extent in a sodium-independent manner. The former process is mediated by NTCP (sodium/bile acid cotransporter) and the latter by OATPs (organic anion transporting polypeptides). OATPs have broad substrate specificity and mediate the uptake of many drugs into hepatocytes. Bile salts are exported from hepatocytes into the biliary tree by BSEP (bile salt export pump). Inhibition of BSEP by drugs or drug metabolites leads to drug-induced cholestasis. BSEP can be inhibited directly from within the hepatocyte or indirectly by a mechanism that first requires canalicular secretion of the perpetrator. In cholestatic liver disease, expression of hepatocellular uptake transporters is generally reduced, while the expression of the canalicular export systems tends to be preserved. This adaptation is controlled by nuclear receptors and transcription factors. Genetic variants of BSEP may be risk factors for drug-induced cholestasis. So far, studies have associated the c.1331 T variant of the ABCB11 gene, encoding a p.V444A substitution in BSEP, as a potential risk factor. Additional risk factors may be genetic variants of uptake transporters or other export transporters for drugs or their metabolites. Bile salts are largely taken up in a sodium-dependent manner and to a minor part in a sodiumindependent manner (into) by hepatocytes. The former process is mediated by the sodium-(dependent) taurocholate cotransporting polypeptide (NTCP) and the latter by the organic anion transporting polypeptides (OATPs). OATPs have a broad substrate specificity and mediate uptake of a many drugs into hepatocytes. Bile salts are exported from hepatocytes into the biliary tree by the bile salt export pump (BSEP). Inhibition of BSEP by drugs or drug metabolites leads to drug-inuduced cholestasis. BSEP can be inhibited directly from within the hepatocyte, or indirectly by a mechanism that first requires canalicular secretion of the perpetrator. In cholestatic liver disease, expression of hepatocellular uptake transporters is generally reduced, while the expression of the canalicular export systems tends to be preserved. This adapatation is controlled by nuclear receptors and transcription factors.

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Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone

Abstract: Abstract

Cited by 46 publications

References 65 publications

Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

Role of the bile salt export pump, BSEP, in acquired forms of cholestasis

Role of Membrane Transport in Hepatotoxicity and Pathogenesis of Drug-Induced Cholestasis

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