[Unexpected liver toxicity of therapeutic drugs: dangerous molecule or hypersensitive patient?].
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Chemical and Drug Induced Liver Injury↗
Biomedical subjects
U A Boelsterli
Publications and source records attributed to U A Boelsterli.
Nimesulide and hepatic adverse effects: roles of reactive metabolites and host factors.
Nimesulide, similar to other nonsteroidal anti-inflammatory drugs (NSAIDs), has been associated with rare and unpredictable but serious hepatic adverse reactions. The low incidence (about 0.1 case per 100,000 treated patients, no more than with most other NSAIDs), estimated from the total number of reported cases relative to the unit sales, plus the fact that the time to onset of liver reactions varied from several days to almost 1 year, suggest that the rare cases of liver injury may be caused by a metabolic idiosyncrasy. This implies that multiple individual host factors affect the toxic potential of nimesulide and/or its metabolites. At the molecular level, reductive bioactivation of the aromatic nitro group might cause oxidoreductive stress and induce covalent binding of, reactive intermediates to proteins. Nimesulide can cause toxicity to mitochondria in vitro, although it is unlikely that the high concentrations required are therapeutically relevant. The mitochondrial toxicity at these supratherapeutic concentrations of nimesulide is characterised by uncoupling of oxidative phosphorylation and opening of the membrane permeability transition pore. Because severe hepatic damage is very rare, and because normally reactive metabolites are readily inactivated or their deleterious effects antagonised, perhaps genetically or environmentally determined alterations in these pathways account for the rare individual susceptibility.
Biotransformation↗
Diabetic KKAy mice exhibit increased hepatic PPARgamma1 gene expression and develop hepatic steatosis upon chronic treatment with antidiabetic thiazolidinediones.
BACKGROUND/AIMS: Peroxisome proliferator-activated receptor-gamma, which is involved in the regulation of lipid homeostasis, is upregulated in the liver of obese and diabetic mice, but the biological consequences of this induction are largely unknown. This study was aimed at further characterizing this upregulation and exploring the downstream biological effects of specific activators on hepatic lipid metabolism. METHODS: Hepatic expression of peroxisome proliferator-activated receptor-gamma1 and gamma2 mRNA and protein was analyzed by real-time polymerase chain reaction and Western immunoblotting in KKAy mice and ob/ob mice. KKAy mice were treated with thiazolidinediones, and hepatic triglyceride content and lipid distribution were analyzed biochemically and by histopathology. RESULTS: KKAy mice exhibited a marked increase in hepatic peroxisome proliferator-activated receptor-gamma1 mRNA and protein levels, whereas the gamma2 isoform was upregulated in ob/ob mice. Treatment of KKAy mice with troglitazone or rosiglitazone resulted in severe microvesicular periacinar steatosis, whereas lean control mice did not develop any pathological liver changes. Hepatic triglyceride levels, however, were not altered by the treatment. CONCLUSIONS: In mice with obesity-associated upregulated hepatic peroxisome proliferator-activated receptor-gamma expression, thiazolidinediones may produce hepatic steatosis. Under pathophysiological conditions, such as non-insulin-dependent diabetes, the liver may thus become sensitized towards peroxisome proliferator-activated receptor-gamma-activating drugs.
Animals↗
Effects of cocaine and its oxidative metabolites on mitochondrial respiration and generation of reactive oxygen species.
Cocaine is capable of producing severe hepatocellular necrosis in laboratory animals and humans. The mechanism of cocaine hepatotoxicity is not well understood, but appears to result from the actions of one or more N-oxidative metabolites of cocaine. Mitochondria have been proposed as critical cellular targets for cocaine toxicity, and previous studies have found depressed mitochondrial respiration and increased mitochondrial generation of reactive oxygen species (ROS) in animals treated with cocaine. To examine the potential role of cocaine N-oxidative metabolites in these effects, mitochondrial respiration and ROS generation were examined in isolated mouse mitochondria treated with cocaine and its N-oxidative metabolites-norcocaine, N-hydroxynorcocaine, and norcocaine nitroxide. Cocaine, in concentrations of 0.25 or 0.5 mM, had no effect on state 3 respiration, state 4 respiration, respiratory control ratio (RCR), or ADP/O ratio. Norcocaine (0.5 mM) inhibited state 3 respiration, and N-hydroxynorcocaine (0.5 mM) inhibited both state 3 and state 4 respiration. Norcocaine nitroxide had the greatest effect on mitochondrial respiration; the lower concentration (0.25 mM) completely inhibited both state 3 and state 4 respiration. Preincubation of mitochondria with cocaine or metabolites increased the inhibitory effect of norcocaine and N-hydroxynorcocaine, but not cocaine. Cocaine, norcocaine, and N-hydroxynorcocaine (0.1 mM) had no effect on ROS generation during state 3 respiration, and cocaine and norcocaine decreased ROS generation under state 4 conditions. Norcocaine nitroxide interfered with the fluorescence ROS assay and could not be assessed. The results suggest that the effects of cocaine on mitochondrial respiration are due to its N-oxidative metabolites. Inhibition of mitochondrial respiration by the N-oxidative metabolites of cocaine may be the underlying cause for observed ATP depletion and subsequent cell death.
Animals↗
Down-regulation by troglitazone of hepatic tumor necrosis factor-alpha and interleukin-6 mRNA expression in a murine model of non-insulin-dependent diabetes.
Troglitazone, a novel thiazolidinedione drug used to treat non-insulin-dependent diabetes mellitus, is a selective ligand for the peroxisome proliferator-activated receptor-gamma (PPARgamma). Recent results indicate that PPARgamma activation by thiazolidinediones regulates adipose tissue- and monocyte/peritoneal macrophage-derived cytokine expression in vitro. We evaluated whether troglitazone may also negatively regulate cytokine expression in the liver, which harbors the majority of the body's resident macrophages but which only weakly expresses PPARgamma. Lean C57BL6 mice and genetically obese KKA(y) mice were chronically treated with troglitazone (100 mg/kg/day for 2 weeks). At the end of treatment, hepatic expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 mRNA was quantitatively determined by kinetic polymerase chain reaction both under basal conditions and after stimulation with lipopolysaccharide (LPS). Both untreated lean and obese mice exhibited low levels of baseline TNF-alpha and IL-6 mRNA expression and responded with a dramatic increase in hepatic cytokine transcripts and TNF-alpha protein expression following a challenge with LPS. Similar to the effects on white adipose tissue, troglitazone not only down-regulated the baseline levels of hepatic TNF-alpha and IL-6, but also greatly attenuated the inducing effects of LPS. The extent of this inhibitory effect of troglitazone was higher in obese KKA(y) mice than in lean mice and was also reflected by markedly down-regulated hepatic TNF-alpha protein expression. These data demonstrate that chronic administration of troglitazone is associated with a greatly attenuated responsiveness towards inducers of hepatic TNF-alpha and IL-6 production. The possible biological consequences of these effects, however, have not yet been assessed.
Animals↗
CYP 450 enzyme induction by chronic oral musk xylene in adult and developing rats.
Developmental and adult toxicity of musk xylene was studied in Long Evans (LE) rats fed with chow containing musk xylene (MX) in food pellets in concentrations of 1 mg, 10 mg, 33 mg, 100 mg and 1000 mg MX per 1 kg chow corresponding to a daily intake of 0.07-0.08 mg MX/kg up to 70-80 mg MX/kg body weight. Adult male and female rats were MX exposed for a minimum of 10 weeks before mating. Exposure continued throughout pregnancy, birth and lactation. The effects of MX on CYP1A1/1A2 were studied in liver microsomes by EROD (7-ethoxyresorufin-rosomes deethylase) for CYP1A1 and by MROD (methoxyresorufin-o-demethylase) for CYP1A2 activity and by Western blotting. MX induced these enzymes dose dependently in adult and developing rats at PN (postnatal day) 1 and 14. The lowest effective maternal dose was 2-3 mg MX/kg/day. Western blot data of CYP2B and CYP3A indicated the induction of both P450 enzyme proteins in developing rats at PN 14 at the higher dose of 70-80 mg MX/kg/day. In contrast, upon high MX exposure CYP2B but not CYP3A was found to be induced in adult first generation male and female rats, indicating differential sensitivity to MX in development.
Administration, Oral↗
Two-dimensional database of mouse liver proteins: changes in hepatic protein levels following treatment with acetaminophen or its nontoxic regioisomer 3-acetamidophenol.
Overdose of acetaminophen (APAP) causes acute hepatotoxicity in rodents and man. The mechanism underlying APAP-induced liver injury remains unclear, but experimental evidence strongly suggests that activation of APAP and subsequent formation of protein adducts are involved in hepatotoxicity. Using proteomics technologies, we constructed a two-dimensional protein database for mouse liver, comprising 256 different gene products and investigated the proteins affected after APAP-induced hepatotoxicity. Adult male mice received a single dose of APAP (100 or 300 mg/kg) or its nontoxic regioisomer 3-acetamidophenol (AMAP, 300 mg/kg). The extent of liver damage was assessed 8 h after administration by increased liver enzyme release and histopathology. Changes in the protein level were studied by comparison of the intensities of the corresponding spots on two-dimensional (2-D) gels. The expression level of about 35 of the identified proteins was modified due to treatment with APAP or AMAP. The observed changes were usually in the order of 10-50% of the control value and were more marked in the high- than in the low-dose of APAP-treated animals. Most of the changes caused by AMAP occurred in a subset of the proteins modified by APAP. Many of the proteins showing changed expression levels are either known targets for covalent modification by N-acetyl-p-benzoquinoneimine (NAPQI) or involved in the regulation of mechanisms that are believed to drive APAP-induced hepatotoxicity.
Acetaminophen↗
CYP 450 enzyme induction by chronic oral musk xylene in adult and developing rats.
Developmental and adult toxicity of musk xylene was studied in Long Evans (LE) rats fed with chow containing musk xylene (MX) in food pellets in concentrations of 1 mg, 10 mg, 33 mg, 100 mg and 1000 mg MX per 1 kg chow corresponding to a daily intake of 0.07-0.08 mg MX/kg up to 70-80 mg MX/kg body weight. Adult male and female rats were MX exposed for a minimum of 10 weeks before mating. Exposure continued throughout pregnancy, birth and lactation. The effects of MX on CYP1A1/1A2 were studied in liver microsomes by EROD (7-ethoxyresorufin-o-deethylase) for CYP1A1 and by MROD (methoxyresorufin-o-demethylase) for CYP1A2 activity and by Western blotting. MX induced these enzymes dose dependently in adult and developing rats at PN (postnatal day) 1 and 14. The lowest effective maternal dose was 2-3 mg MX/kg/day. Western blot data of CYP2B and CYP3A indicated the induction of both P450 enzyme proteins in developing rats at PN 14 at the higher dose of 70-80 mg MX/kg/day. In contrast, upon high MX exposure CYP2B but not CYP3A was found to be induced in adult first generation male and female rats, indicating differential sensitivity to MX in development.
Administration, Oral↗
Synthesis and biodistribution of a short nonionic oligonucleotide analogue in mouse with a potential to mimic peptides.
A nonionic RNA analogue of the sequence r(USO2GSO2ASO2C) has been synthesized where each bridging phosphate diester is replaced by a dimethylene sulfone unit (rSNA). The rSNA was synthesized in solution from 3',5'-bishomo-beta-ribonucleoside derivatives as building blocks. Full experimental procedures are provided, and the product and all synthetic intermediates are fully characterized. The tetramer is nonionic but highly dipolar due to multiple hydrogen bonding opportunities. It is freely soluble in water only at higher pH's, permitting it to be radiolabeled by exchange of the acidic protons alpha to the sulfones with tritiated water. The tritiated molecule was administered intravenously into the tail vein (2.6 mg/kg) of mice, and its distribution was monitored over 48 h. The rSNA was widely distributed in the biological tissues, including the brain, and excreted in both the feces and the urine. The accumulation of radioactivity was significantly higher in liver and kidney than in other tissues. Radiolabel was recovered from the urine, analyzed by HPLC, and shown to be intact oligonucleotide sulfone. This is the first bioavailability study on a short nonionic oligonucleotide analogue, a class of molecules with potential biomedical applications.
Animals↗
Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-alpha gene knockout mice.
Recent evidence suggests that macrophages and/or other nonparenchymal cells may release important mediators contributing to the hepatic necrosis induced by high doses of acetaminophen (APAP). The nature and causative role of these mediators has remained elusive, however. To investigate the role of the proinflammatory cytokine, tumor necrosis factor (TNF) in the initiation and early propagation of APAP-induced liver injury, we have used mice deficient in both TNF and the closely related lymphotoxin-alpha (LT-alpha). Male TNF/LT-alpha knockout mice and C57BL/6 wild-type mice were treated with a hepatotoxic dose of APAP (400 mg/kg, intraperitoneally), and the development of liver injury was monitored over 8 hours. Both genotypes exhibited similar basal activities of hepatic cytochrome P450 2E1 and 1A2. After APAP administration, both the rate of glutathione consumption and the extent of subsequent selective protein binding did not differ significantly in the knockout and wild-type mice. The TNF/LT-alpha-deficient mice developed severe centrilobular necrosis and exhibited highly increased levels of serum alanine aminotransferase and aspartate aminotransferase, the extent of which was not significantly different from that in wild-type mice. In C57BL/6 mice exposed to APAP, no increases in hepatic transcripts of TNF or LT-alpha were found by reverse transcription-polymerase chain reaction, nor was immunoreactive serum TNF detected by enzyme-linked immunosorbent assay over 8 hours posttreatment. These data indicate that, in the absence of the genes encoding for TNF and LT-alpha, APAP bioactivation was not altered and mice still developed severe hepatic necrosis. Thus, TNF is unlikely to be a key mediator in the early pathogenesis of APAP-induced hepatotoxicity.
Acetaminophen↗
Antioxidant and cytoprotective properties of D-tagatose in cultured murine hepatocytes.
D-Tagatose is a zero-energy producing ketohexose that is a powerful cytoprotective agent against chemically induced cell injury. To further explore the underlying mechanisms of cytoprotection, we investigated the effects of D-tagatose on both the generation of superoxide anion radicals and the consequences of oxidative stress driven by prooxidant compounds in intact cells. Primary cultures of hepatocytes derived from male C57BL/6 mice were exposed to the redox cycling drug nitrofurantoin (NFT). Lethal cell injury induced by 300 microM NFT was completely prevented by high concentrations (20 mM) of D-tagatose, whereas equimolar concentrations of glucose, mannitol, or xylose were ineffective. The extent of NFT-induced intracellular superoxide anion radical formation was not altered by D-tagatose, indicating that the ketohexose did not inhibit the reductive bioactivation of NFT. However, the NFT-induced decline of the intracellular GSH content was largely prevented by D-tagatose. The sugar also afforded complete protection against NFT toxicity in hepatocytes that had been chemically depleted of GSH. Furthermore, the ketohexose fully protected from increases in both membrane lipid peroxidation and protein carbonyl formation. In addition, D-tagatose completely prevented oxidative cell injury inflicted by toxic iron overload with ferric nitrilotriacetate (100 microM). In contrast, D-tagatose did not protect against lethal cell injury induced by tert-butyl hydroperoxide, a prooxidant which acts by hydroxyl radical-independent mechanisms and which is partitioned in the lipid bilayer. These results indicate that D-tagatose, which is a weak iron chelator, can antagonize the iron-dependent toxic consequences of intracellular oxidative stress in hepatocytes. The antioxidant properties of D-tagatose may result from sequestering the redox-active iron, thereby protecting more critical targets from the damaging potential of hydroxyl radical.
Animals↗
Diclofenac acyl glucuronide, a major biliary metabolite, is directly involved in small intestinal injury in rats.
BACKGROUND & AIMS: Enterohepatic recirculation of nonsteroidal anti-inflammatory drugs is a critical factor in the pathogenesis of intestinal injury, but the underlying mechanism of toxicity remains obscure. The aim of this study was to examine the role of diclofenac acyl glucuronide, which is the major biliary metabolite and is chemically reactive, in the precipitation of small intestinal ulceration. METHODS: Hepatocanalicular conjugate export pump-deficient (TR-) rats were used to selectively block diclofenac enterohepatic circulation without interrupting bile flow. Bile from diclofenac-treated normal rats was orally transferred to wild-type and TR- rats, and the extent of ulcer formation was compared with that induced by control bile containing free diclofenac. The effect of induction of hepatic diclofenac glucuronosyltransferase on the severity of diclofenac-induced ulceration was also determined. RESULTS: TR- rats were refractory to diclofenac given either intraperitoneally or perorally. However, transfer of bile containing diclofenac glucuronide significantly increased the extent of ulcer formation in both normal and TR- rats. Moreover, induction of glucuronosyltransferase aggravated intestinal ulceration. CONCLUSIONS: The reactive acyl glucuronide of diclofenac, or the acyl glucuronide of one of its oxidative metabolites, is directly involved in the pathogenesis of small intestinal injury.
Animals↗
Selective protein adduct formation of diclofenac glucuronide is critically dependent on the rat canalicular conjugate export pump (Mrp2).
Previous work demonstrates that the reactive acyl glucuronide of the nonsteroidal antiinflammatory drug diclofenac forms selective protein adducts in the liver, which may play a causal role in the pathogenesis of diclofenac-associated liver toxicity. Because glucuronide conjugates can be exported into the bile, we explored the role of diclofenac glucuronide hepatobiliary transport in the formation of site-specific protein adducts. Specifically, to analyze intracellular (hepatocytes) versus extracellular (biliary tree) targeting of proteins, we have compared the pattern of diclofenac binding in normal Wistar rats with that in mutant transport-deficient (TR-) rats which lack the functional canalicular isoform of the conjugate export pump, Mrp2. In bile duct-cannulated normal rats, >50% of an iv injected dose of [14C]diclofenac appeared in the bile over a 90-min period. In contrast, in TR- rats virtually no hepatobiliary excretion of diclofenac glucuronide was found. After administration of diclofenac (30 mg/kg/day, ip for 3 days) to rats of both genotypes, a major protein adduct of an apparent molecular mass of 118 kDa was selectively detected by immunoblotting in isolated canalicular, but not in basolateral, membrane subfractions of wild-type rats, whereas no plasma membrane adducts could be found in the livers of TR- rats. Furthermore, immunohistochemical analysis using an anti-diclofenac antibody revealed the presence of distinct diclofenac-modified proteins on canalicular membranes of liver sections from diclofenac-treated normal rats, whereas no adducts could be identified in livers of TR- rats. In Western blots, the major diclofenac-modified canalicular membrane protein did not comigrate with Mrp2, indicating that the glucuronide carrier itself was unlikely to be a target. Collectively, the results demonstrate that the reactive diclofenac glucuronide is selectively transported into bile via Mrp2 and that hepatobiliary transport is critical for diclofenac covalent binding to proteins in the biliary tree.
Animals↗
The labile iron pool in hepatocytes: prooxidant-induced increase in free iron precedes oxidative cell injury.
The labile iron pool (LIP) represents the nonferritin-bound, redox-active iron that has been implicated in oxidative stress and cell injury. Here we examined whether alterations in LIP can be detected in cultured murine hepatocytes and whether increases in LIP are related to the oxidative damage inflicted by the redox cycling drug nitrofurantoin (NFT). Early changes in LIP were monitored with the metal-sensitive fluorescent probe calcein (CA), the fluorescence of which is quenched on binding to iron. Short-term exposure (<1 h) to NFT reduced the CA fluorescence signal by 30%, indicating that the amount of LIP-associated iron had increased. Prolonged exposure (2 h) to NFT caused oxidative cell injury. The addition of the cell-permeable ferrous iron chelator 2,2'-bipyridyl not only prevented the quenching of CA fluorescence but also partially protected from NFT toxicity. It is concluded that reductive stress-induced increase in LIP is an essential event that precedes oxidative cell damage in intact hepatocytes.
2,2'-Dipyridyl↗
Fructose and tagatose protect against oxidative cell injury by iron chelation.
To further investigate the mechanism by which fructose affords protection against oxidative cell injury, cultured rat hepatocytes were exposed to cocaine (300 microM) or nitrofurantoin (400 microM). Both drugs elicited massively increased lactate dehydrogenase release. The addition of the ketohexoses D-fructose (metabolized via glycolysis) or D-tagatose (poor glycolytic substrate) significantly attenuated cocaine- and nitrofurantoin-induced cell injury, although both fructose and tagatose caused a rapid depletion of ATP and compromised the cellular energy charge. Furthermore, fructose, tagatose, and sorbose all inhibited in a concentration-dependent manner (0-16 mM) luminolenhanced chemiluminescence (CL) in cell homogenates, indicating that these compounds inhibit the iron-dependent reactive oxygen species (ROS)-mediated peroxidation of luminol. Indeed, both Fe2+ and Fe3+ further increased cocaine-stimulated CL, which was markedly quenched following addition of the ketohexoses. The iron-independent formation of superoxide anion radicals (acetylated cytochrome c reduction) induced by the prooxidant drugs remained unaffected by fructose or tagatose. The iron-chelator deferoxamine similarly protected against prooxidant-induced cell injury. In contrast, the nonchelating aldohexoses D-glucose and D-galactose did not inhibit luminol CL nor did they protect against oxidative cell injury. These data indicate that ketohexoses can effectively protect against prooxidant-induced cell injury, independent of their glycolytic metabolism, by suppressing the iron-catalyzed formation of ROS.
Adenosine Triphosphate↗
Cytotoxic activity of T cells and non-T cells from diclofenac-immunized mice against cultured syngeneic hepatocytes exposed to diclofenac.
To evaluate whether hepatocellular protein adducts of the nonsteroidal antiinflammatory drug diclofenac could elicit a specific cell-mediated or antibody-dependent immune response that eventually results in liver cell destruction, we developed a murine ex vivo/in vitro mixed lymphocyte hepatocyte culture (MLHC) model. C57BL/6 mice were immunized either with diclofenac conjugated to keyhole limpet hemocyanin (KLH) or with KLH alone. Splenocytes from mice exhibiting hgih antidiclofenac antibody titers were isolated and co-cultured at an effector/target cell ratio of 100:1 with syngeneic murine hepatocytes preexposed to diclofenac. By 48 and 72 hours, extracellular alanine transaminase (ALT) activity had increased 6.4- and 7.6-fold, respectively, versus the 24-hour value. In contrast, there was no significant cytotoxic response after either drug treatment alone or immunization alone. Furthermore, those cellular populations capable of inducing ALT release also showed lymphocyte stimulation as determined by interleukin-2 (IL-2) receptor expression and lymphocyte proliferation analysis. The extent of cell injury was highest in the presence of lymphocytes highly enriched in T cells and was reduced by 40% in the presence of anti-MHC I antibodies. Similarly, albeit to a lesser extent, non-T cell-enriched lymphocyte fractions also induced hepatocyte injury. The addition of co-culture supernatants to hepatocytes had no effect, thus ruling out the possibility that soluble factors alone mediated the cell injury. However, supernatants from diclofenac-stimulated lymphocytes, combined with nonstimulated splenocytes, triggered an immediate (< 1 hour) cytotoxic response, suggesting antibody-dependent cell-mediated mechanisms of target cell injury. These results indicate that diclofenac-treated hepatocytes carried antigenic determinants that were recognized by T cells and non-T cells derived from diclofenac/KLH-immunized mice, resulting in cell-mediated destruction of the target hepatocytes.
Animals↗
Identification and characterization of a basolateral dicarboxylate/cholate antiport system in rat hepatocytes.
The mechanisms and driving forces for the uptake of the unconjugated bile acid cholate were investigated both in cultured rat hepatocytes and in rat liver basolateral (sinusoidal) plasma membrane (BLPM) vesicles. Determination of initial uptake rates of [3H]cholate (0.1 microM) into cultured hepatocytes confirmed that the majority (75%) of the transmembrane transport was mediated by Na(+)-independent mechanisms. This portion of cholate uptake consisted of a pH-sensitive moiety representing nonionic diffusion, which may become quantitatively important at low pH and high cholate concentrations, as well as of a saturable (Michaelis constant 7.4 microM), 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS)-sensitive transport moiety, suggesting the involvement of a carrier. This latter transport system was functionally characterized by 1) inhibition of cellular cholate uptake in the absence of extracellular sodium by the dicarboxylic acid alpha-ketoglutarate (alpha-KG; 1 mM) and by the organic anion p-aminohippurate (PAH; 1 mM); 2) stimulation of cellular cholate uptake by alpha-KG (10 microM) or PAH (1 mM) in the presence of an inwardly directed sodium gradient; 3) lack of sensitivity toward lithium in BLPM vesicles; 4) trans-stimulation of vesicular cholate uptake by alpha-KG or PAH, but not by benzoate; and 5) cis-inhibition of alpha-KG/alpha-KG self-exchange by extravesicular cholate (400 microM), PAH (5 mM), probenecid, or DIDS. Collectively, these data indicate the presence of a Na(+)-dicarboxylate cotransport-coupled organic anion exchanger in the hepatocyte basolateral plasma membrane that may be involved in cholate uptake in the liver.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Idiosyncratic liver toxicity of nonsteroidal antiinflammatory drugs: molecular mechanisms and pathology.
This review explores the clinical hepatic pathology associated with the use of nonsteroidal antiinflammatory drugs (NSAIDs), possible cellular and molecular mechanisms of injury, and future challenges. NSAIDs comprise a group of widely used compounds that have been associated with rare adverse reactions in the liver, including fulminant hepatitis and cholestasis. These reactions are idiosyncratic, mostly independent of the dose administered, and host-dependent. The mechanisms responsible for the initiation and perpetuation of NSAID-induced hepatotoxicity remain poorly understood and have been largely inferred from clinical manifestation. A mounting body of evidence, however, indicates that many acidic NSAIDs are metabolized to reactive acyl glucuronides that can form covalent adducts with plasma proteins and hepatocellular proteins. In hepatocytes cocultured with lymphocytes, these NSAID-altered proteins can become antigenic. Thus, long-lived, drug-altered proteins may act as immunogens and produce cytotoxic T-cell-mediated or antibody-dependent, cell-mediated toxicity in susceptible patients. Alternatively, individual abnormalities in metabolism or disposition of some NSAIDs may lead to the formation or accumulation of toxic metabolites. Additional work with transgenic animal models is needed to permit better understanding of the general and specific risk factors involved in the pathogenesis of the idiosyncratic liver injuries related to NSAIDs and other drugs.
Animals↗