Drug–Induced Liver Injury: Mechanisms and Test Systems

Bissell, D. Montgomery; Gores, Gregory J.; Laskin, Debra L.; Hoofnagle, Jay H.

doi:10.1053/jhep.2001.23505

Cited by 237 publications

(153 citation statements)

References 42 publications

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“…It was speculated that enhanced accumulation in troglitazone in the liver of poor metabolizers might attenuate ⌬⌿ m in hepatocytes, triggering subsequent events for severe hepatic damage, although candidate genetic mutations in the metabolic enzymes in the poor metabolizers, such as CYP2C8, CYP3A4, and CYP2C19, have not yet been determined. 42 Among 3 PPAR␥ ligands used in this study, troglitazone caused the severest attenuation in unit ⌬⌿ m , in concert with marked enlargement in the mitochondria. The similar functional and morphologic alterations in the mitochondria have previously been recognized during terminal differentiation and apoptosis in intestinal cells, 15 allowing us to further examine differentiation-inducing potential of troglitazone on hepatocytes.…”

Section: Discussionmentioning

confidence: 79%

Hydrogen peroxide overproduction in megamitochondria of troglitazone-treated human hepatocytes

Shishido

2003

Hepatology

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Troglitazone has been withdrawn from therapeutic options for diabetes mellitus because of its severe hepatocyte toxicity of unknown pathogenesis. The aim of the present study was to assess both morphologic and functional alterations in the mitochondria of troglitazonetreated hepatocytes. A polarized human hepatocyte cell line, OUMS-29, was used in this study. The mitochondrial volume and the mitochondrial transmembrane potential (⌬⌿ m ) were examined using flow cytometry with nonylacridine orange (NAO) and rhodamine-123, respectively. An ultrastructural examination of the troglitazone-treated OUMS-29 cells was performed using transmission electron microscopy (TEM). Reactive oxygen species (ROS) production was assessed using flow cytometry with dihydroethidium and 2 ,7 -dichlorodihydrofluorescein diacetate. A significant increase in the mitochondrial volume of the troglitazone-treated cells was found by the NAO analysis, in comparison with pioglitazone-treated and ciglitazone-treated cells. The increase in volume was due to a marked enlargement in the mitochondria. The markedly enlarged mitochondria with intramitochondrial electrondense deposits were confirmed on TEM, which showed myelin-like structures, indicating degraded membrane constituents. The troglitazone-treated cells showed a significant decline in the ⌬⌿ m per unit mitochondrial volume but resulted in no clear cell death. ROS analysis revealed a significant production of hydrogen peroxide in the troglitazone-treated hepatocytes. This production was attenuated using an antioxidant, N-acetyl-L-cysteine. In conclusion, troglitazone caused overproduction of hydrogen peroxide, which deteriorated both mitochondrial membrane structures and mitochondrial function, leading to a possible priming for the severe hepatocyte toxicity. (HEPATOLOGY 2003;37:136-147.) T roglitazone, a ligand for peroxisome proliferatoractivated receptor ␥ (PPAR␥), used to be administered as an antidiabetic drug until it was discovered to be associated with hepatotoxicity and withdrawn from the market after reports of several dozens of deaths or cases of severe hepatic failure requiring liver transplantation. 1,2 In contrast to troglitazone, 2 other glitazones, pioglitazone and rosiglitazone, are still on the market; however, several cautionary reports have suggested that the latter 2 drugs show hepatotoxicity as a class effect of glitazones. [2][3][4][5][6][7][8][9] Although the troglitazone-associated hepatotoxicity has been considered idiosyncratic direct hepatocyte toxicity, 10 the precise mechanism has remained unclear. In our recent study, mitochondrial damage was ultrastructurally demonstrated in troglitazone-treated human hepatoma cells, 11 allowing us to first focus on alterations in the mitochondrial structure and the function in the troglitazone-treated human hepatocytes. Troglitazone is known

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Section: Discussionmentioning

confidence: 79%

Hydrogen peroxide overproduction in megamitochondria of troglitazone-treated human hepatocytes

Shishido

2003

Hepatology

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“…ALT and AST elevations may be absent, mild or moderate. Late histological findings include bile ductular proliferation, cholestasis and fibrosis [27][28][29]. Although microvesicular steatosis is looked for as a pathognomonic sign of this disorder, small vesicles can coalesce into macrovesicular fat [30].…”

Section: Summary Of Clinical Resultsmentioning

confidence: 99%

Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone

Julie

Kende

et al. 2008

Diabetologia

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“…Drug dosing can be limited by toxicity to a clearance organ such as the liver (35,36). The apparent splenic clearance of RBCMs affords the possibility of different dosing restrictions if these particles were to be used as drug carriers because of the low concentrations found in the liver, as well as the possibility for direct treatment or imaging of the spleen.…”

Section: Compartmental Analysis Of Rbcm Circulation Profile After Intmentioning

confidence: 99%

Using mechanobiological mimicry of red blood cells to extend circulation times of hydrogel microparticles

Merkel¹,

Jones

Herlihy³

et al. 2011

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

488

435

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It has long been hypothesized that elastic modulus governs the biodistribution and circulation times of particles and cells in blood; however, this notion has never been rigorously tested. We synthesized hydrogel microparticles with tunable elasticity in the physiological range, which resemble red blood cells in size and shape, and tested their behavior in vivo. Decreasing the modulus of these particles altered their biodistribution properties, allowing them to bypass several organs, such as the lung, that entrapped their more rigid counterparts, resulting in increasingly longer circulation times well past those of conventional microparticles. An 8-fold decrease in hydrogel modulus correlated to a greater than 30-fold increase in the elimination phase half-life for these particles. These results demonstrate a critical design parameter for hydrogel microparticles.biomimetic | deformability | drug carriers | long circulating | red blood cell mimic

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Drug–Induced Liver Injury: Mechanisms and Test Systems

Cited by 237 publications

References 42 publications

Hydrogen peroxide overproduction in megamitochondria of troglitazone-treated human hepatocytes

Hydrogen peroxide overproduction in megamitochondria of troglitazone-treated human hepatocytes

Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone

Using mechanobiological mimicry of red blood cells to extend circulation times of hydrogel microparticles

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