Evaluation Of Hepatotoxicity Research Articles

Evaluation of CYP3A4 inhibition and hepatotoxicity using DMSO-treated human hepatoma HuH-7 cells.

A human hepatoma cell line (HuH-7) was evaluated as a metabolically competent cell model to investigate cytochrome P450 3A4 (CYP3A4) inhibition, induction, and hepatotoxicity. First, CYP3A4 gene expression and activity were determined in HuH-7 cells under three culture conditions: 1-week culture, 3-week culture, or 1% dimethyl sulfoxide (DMSO) treatment. HuH-7 cells treated with DMSO for 2weeks after confluence expressed the highest CYP3A4 gene expression and activity compared to the other two culture conditions. Furthermore, CYP3A4 activity in DMSO-treated HuH-7 cells was compared to that in a human hepatoma cell line (HepG2/C3A) and human bipotent progenitor cell line (HepaRG), which yielded the following ranking: HepaRG > DMSO-treated HuH-7 >> HepG2/C3A cells. The effects of three known CYP3A4 inhibitors were evaluated using DMSO-treated HuH-7 cells. CYP3A4 enzyme inhibition in HuH-7 cells was further compared to human recombinant CYP3A4, indicating similar potency for reversible inhibitors (IC 50 within 2.5-fold), but different potency for the irreversible inhibitor. Next, induction of CYP3A4 activity was compared between DMSO-treated HuH-7 and HepaRG cells using two known inducers. DMSO-treated HuH-7 cells yielded minimal CYP3A4 induction compared to that in the HepaRG cells after 48-h treatments. Finally, the cytotoxicity of five known hepatotoxicants was evaluated in DMSO-treated HuH-7, HepG2/C3A, and HepaRG cells, and significant differences in cytotoxic sensitivity were observed. Overall, DMSO-treated HuH-7 cells are a valuable model for medium- or high-throughput screening of chemicals for CYP3A4 inhibition and hepatotoxicity.

Muse細胞由来肝細胞の肝毒性・薬物動態評価系としての有用性―マイクロRNAを用いたMuse細胞由来肝前駆細胞の成熟化方法の確立―

Muse細胞由来肝細胞の肝毒性・薬物動態評価系としての有用性―マイクロRNAを用いたMuse細胞由来肝前駆細胞の成熟化方法の確立―

ヒト肝細胞キメラマウスに由来する新鮮ヒト肝細胞（PXB-cells）の性状解析及びstatinの肝毒性評価への応用

ヒト肝細胞キメラマウスに由来する新鮮ヒト肝細胞（PXB-cells）の性状解析及びstatinの肝毒性評価への応用

High-content screening imaging and real-time cellular impedance monitoring for the assessment of chemical’s bio-activation with regards hepatotoxicity

Testing hepatotoxicity is a crucial step in the development and toxicological assessment of drugs and chemicals. Bio-activation can lead to the formation of metabolites which may present toxicity for the organism. Classical cytotoxic tests are not always appropriate and are often insufficient, particularly when non metabolically-competent cells are used as the model system, leading to false-positive or false-negative results. We tested over 24h the effects of eight reference compounds on two different cell models: primary cultures of rat hepatocytes and FAO hepatoma cells that lack metabolic properties. We performed inter-assay validation between three classical cytotoxicity assays and real-time cell impedance data. We then complemented these experiments with high-content screening (HCS) to determine the cell function disorders responsible for the observed effects. Among the different assays used, the neutral red test seemed to be well suited to our two cell models, coupled with real-time cellular impedance which proved useful in the detection of bio-activation. Indeed, impedance monitoring showed a high sensitivity with interesting curve profiles yet seemed unsuitable for evaluation of viability on primary culture. Finally, HCS in the evaluation of hepatotoxicity is likely to become an essential tool for use in parallel to a classical cytotoxic assay in the assessment of drugs and environmental chemicals.

Evaluation of Adverse Drug Properties with Cryopreserved Human Hepatocytes and the Integrated Discrete Multiple Organ Co-culture (IdMOC(TM)) System.

Human hepatocytes, with complete hepatic metabolizing enzymes, transporters and cofactors, represent the gold standard for in vitro evaluation of drug metabolism, drug-drug interactions, and hepatotoxicity. Successful cryopreservation of human hepatocytes enables this experimental system to be used routinely. The use of human hepatocytes to evaluate two major adverse drug properties: drug-drug interactions and hepatotoxicity, are summarized in this review. The application of human hepatocytes in metabolism-based drug-drug interaction includes metabolite profiling, pathway identification, P450 inhibition, P450 induction, and uptake and efflux transporter inhibition. The application of human hepatocytes in toxicity evaluation includes in vitro hepatotoxicity and metabolism-based drug toxicity determination. A novel system, the Integrated Discrete Multiple Organ Co-culture (IdMOC) which allows the evaluation of nonhepatic toxicity in the presence of hepatic metabolism, is described.

Effect of amlodipine, lisinopril and allopurinol on acetaminophen-induced hepatotoxicity in rats

BackgroundExposure to chemotherapeutic agents such as acetaminophen may lead to serious liver injury. Calcium deregulation, angiotensin II production and xanthine oxidase activity are suggested to play mechanistic roles in such injury. ObjectiveThis study evaluates the possible protective effects of the calcium channel blocker amlodipine, the angiotensin converting enzyme inhibitor lisinopril, and the xanthine oxidase inhibitor allopurinol against experimental acetaminophen-induced hepatotoxicity, aiming to understand its underlying hepatotoxic mechanisms. Material and methodsAnimals were allocated into a normal control group, a acetaminophen hepatotoxicity control group (receiving a single oral dose of acetaminophen; 750mg/kg/day), and four treatment groups receive N-acetylcysteine (300mg/kg/day; a reference standard), amlodipine (10mg/kg/day), lisinopril (20mg/kg/day) and allopurinol (50mg/kg/day) orally for 14 consecutive days prior to acetaminophen administration. Evaluation of hepatotoxicity was performed by the assessment of hepatocyte integrity markers (serum transaminases), oxidative stress markers (hepatic malondialdehyde, glutathione and catalase), and inflammatory markers (hepatic myeloperoxidase and nitrate/nitrite), in addition to a histopathological study. ResultsRats pre-treated with amlodipine, lisinopril or allopurinol showed significantly lower serum transaminases, significantly lower hepatic malondialdehyde, myeloperoxidase and nitrate/nitrite, as well as significantly higher hepatic glutathione and catalase levels, compared with acetaminophen control rats. Serum transaminases were normalized in the lisinopril treatment group, while hepatic myeloperoxidase was normalized in the all treatment groups. Histopathological evaluation strongly supported the results of biochemical estimations. ConclusionAmlodipine, lisinopril or allopurinol can protect against acetaminophen-induced hepatotoxicity, showing mechanistic roles of calcium channels, angiotensin converting enzyme and xanthine oxidase enzyme in the pathogenesis of hepatotoxicity induced by acetaminophen.

Hepatotoxicity associated with agomelatine and other antidepressants: Disproportionality analysis using pooled pharmacovigilance data from the Uppsala Monitoring Centre.

Since its marketing approval, the attention to the hepatic side-effect profile of the antidepressant agomelatine (AGM) has gradually increased. Several cases of severe hepatotoxic adverse drug reactions (ADR) have been reported and the European Medicines Agency has released a safety warning regarding AGM-associated hepatotoxicity. However, there are insufficient data for an adequate safety assessment of AGM-related hepatotoxicity. Therefore, we performed a quantitative signal detection analysis using pharmacovigilance data from the Uppsala Monitoring Centre from the WHO that records ADR data from worldwide sources; we calculated reporting odds ratios (ROR) as measures for disproportionality within a case/non-case approach for AGM and several other antidepressants. AGM was statistically associated with an increased risk of hepatotoxicity (ROR 6.4 [95%CI 5.7-7.2]) as well as both positive controls: amineptine (ROR 38.4 [95%CI 33.8-43.6]) and nefazodone (ROR 3.2 [95%CI 3.0-3.5]). Following amineptine, AGM was associated with the second highest ROR, followed by tianeptine (ROR 4.4 [95%CI 3.6-5.3]), mianserin (ROR 3.6 [95%CI 3.3-3.9]), and nefazodone. These results support the hypothesis that AGM is associated with relevant hepatotoxicity. However, the used data and applied method do not allow a quantitative evaluation of hepatotoxicity or assessment of substance-specific differences regarding the extent of hepatotoxicity.

Hepatotoxic potential of asarones: in vitro evaluation of hepatotoxicity and quantitative determination in herbal products.

α and β asarones are natural constituents of some aromatic plants, especially species of the genus Acorus (Araceae). In addition to reports of beneficial properties of asarones, genotoxicity and carcinogenicity are also reported. Due to potential toxic effects of β-asarone, a limit of exposure from herbal products of ~2 μg/kg body weight/day has been set temporarily until a full benefit/risk assessment has been carried out by the European Medicines Agency. Therefore, it is important to monitor levels of β-asarone in herbal products. In this study, we developed a simple, rapid and validated GC-MS method for quantitative determination of asarones and applied it in 20 pediatric herbal products after detecting high concentrations of β-asarone in a product suspected to be implicated in hepatotoxicity in a 3 month old infant. Furthermore, targeted toxicological effects were further investigated in human hepatocytes (THLE-2 cells) by employing various in vitro assays, with the goal of elucidating possible mechanisms for the observed toxicity. Results showed that some of the products contained as much as 4–25 times greater amounts of β-asarone than the recommended levels. In 4 of 10 samples found to contain asarones, the presence of asarones could not be linked to the labeled ingredients, possibly due to poor quality control. Cell-based investigations in THLE-2 cells confirmed the cytotoxicity of β-asarone (IC50 = 40.0 ± 2.0 μg/mL) which was associated with significant lipid peroxidation and glutathione depletion. This observed cytotoxic effect is likely due to induction of oxidative stress by asarones. Overall, the results of this study ascertained the usability of this GC-MS method for the quantitative determination of asarones from herbal products, and shed light on the importance of controlling the concentration of potentially toxic asarones in herbal products to safeguard consumer safety, especially when the target consumers are young children. Further investigations of the toxicity of asarones are warranted.

Synthesis and dose interval dependent hepatotoxicity evaluation of intravenously administered polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticle on Wistar rats

Superparamagnetic iron oxide nanoparticles are being used in medical imaging, drug delivery, cancer therapy, and so on. However, there is a direct need to identify any nanotoxicity associated with these nanoparticles. However uncommon, drug-induced liver injury (DILI) is a major health concern that challenges pharmaceutical industry and drug regulatory agencies alike. In this study we have synthesized and evaluated the dose interval dependent hepatotoxicity of polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticles (PUSPIOs). To assess the hepatotoxicity of intravenously injected PUSPIOs, alterations in basic clinical parameters, hematological parameters, hemolysis assay, serum levels of liver marker enzymes, serum and liver lipid peroxidation (LPO) levels, enzymatic antioxidant levels, and finally histology of liver, kidney, spleen, lung, brain, and heart tissues were studied in control and experimental Wistar rat groups over a 30-day period. The results of our study showed a significant increase in the aspartate transaminase (AST) enzyme activity at a dose of 10mg/kg b.w. PUSPIOs twice a week. Besides, alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) enzyme activity showed a slender increase when compared with control experimental groups. A significant increase in the serum and liver LPO levels at a dose of 10mg/kg b.w. PUSPIOs twice a week was also observed. Histological analyses of liver, kidney, spleen, lung, brain and heart tissue samples showed no obvious uncharacteristic changes. In conclusion, PUSPIOs were found to posses excellent biocompatibility and Wistar rats showed much better drug tolerance to the dose of 10mg/kg b.w. per week than the dose of 10mg/kg b.w. twice a week for the period of 30 days.

Safety and tolerability of agomelatine: focus on hepatotoxicity.

Hepatotoxicity related to antidepressive pharmacotherapy is a major safety concern, particularly considering that severe forms of hepatic failure with fatal outcome have been reported. Severe hepatotoxic adverse drug reactions were also reported for agomelatine (AGM), an antidepressive agent, which was approved for the treatment of major depressive disorder (MDD) in adults by the European Medicines Agency (EMA) in February 2009. Its general safety and tolerability profile appears to be favourable or similar in comparison to other antidepressants, particularly regarding metabolic aspects, sexual functioning, gastrointestinal side effects, and discontinuation phenomena. Epidemiology and pathophysiology of AGM-related hepatotoxicity are currently poorly understood. Pooled data from clinical trials indicate that patients treated with AGM demonstrate increased prevalence rates of elevated liver transaminases (> 3 x ULN; 1.34% on AGM 25 mg/day, 2.51% on AGM 50 mg/day) in comparison to placebo (0.5%). AGM-related hepatotoxic adverse drug reactions are unpredictable and usually occur as asymptomatic increases of liver enzymes, which develop during the first months of treatment and mostly recover after discontinuation of AGM-treatment or even on continued treatment. Liver injury due to AGM-related hepatotoxicity is mostly hepatocellular. The underlying mechanism appears to be idiosyncratic. Cholestatic or hypersensitivity reactions have not yet been reported. Some evidence suggests dose-dependence of AGM-related hepatotoxicity. In a recent post-authorisation opinion of the EMA, hepatotoxic reactions related to AGM were declared as an important identified risk and new contraindications for treatment with AGM were released (hypersensitivity to AGM, elevations of liver enzymes > 3 x ULN, hepatic impairment (not further specified), parallel use of potent CYP1A2 inhibitors). Considering these aspects, treatment with AGM must only be performed under strict accordance with the recently modified prescribing information. A final evaluation of AGM-related hepatotoxicity is currently not possible; further studies are necessary.

A ready-to-use, versatile, multiplex-able three-dimensional scaffold-based immunoassay chip for high throughput hepatotoxicity evaluation.

Hydrogel as three-dimensional (3D) substrate has been employed in miniaturized high throughput protein detection platforms to increase the number of effective antibodies and signal augmentation. However, the high water content of the hydrogel can dilute samples and create barrier to mass transfer, limiting hydrogel height to several microns in most platforms. Moreover, these platforms cannot achieve widespread use in common laboratories as they usually rely heavily on expensive robotic liquid handlers and custom-built components. Here we developed a ready-to-use, easy to store and handle, versatile and multiplex-able 3D scaffold-based immunoassay chip (3D immunoChip) possible for high throughput protein quantification using bench-top equipment in common laboratories. Sample dilution, mass transfer, signal scattering and storage problems can be avoided by using dry scaffolds that regain transparency upon rehydration. When combined with hydrophilic-hydrophobic patterned reagent loading slides, manual high throughput handling of samples can be achieved. As these micro-scaffolds are patterned without barriers in between, simultaneous and effortless washing of all the reaction zones is possible in a Petri dish. Such features aid the 3D immunoChip in saving up to 100 times reagent and about 6 times labour. The 3D immunoChip is able to detect albumin (ALB), as a model analyte, from 5 ng mL(-1) to 1000 ng mL(-1), making it comparable to the commercialized ELISA kit based on a 96-well plate (0.22-400 ng mL(-1)). This thus enables the 3D immunoChip to directly detect ALB secreted by HepaRG cells cultured in a 3D cell culture array chip for high throughput drug hepatotoxicity evaluation, which could potentially accelerate drug screening.

Utility of human hepatocyte spheroids for evaluation of hepatotoxicity

Utility of human hepatocyte spheroids for evaluation of hepatotoxicity

Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: current status and challenges.

Prompted by approval in 1997 of troglitazone and bromfenac, two drugs that promptly began to show serious and sometimes fatal liver toxicity, we began at the Food and Drug Administration (FDA) a series of annual conferences in 1999 to consider issues of drug-induced liver injury (DILI). First inviting reviewers of new drug applications we opened the audiences in 2001 to pharmaceutical industry and academic consultants to industry and FDA, and slides shown at the meetings were posted on the internet to be available at the website of the American Association for the Study of Liver Diseases (AASLD)–go to (http://www.aasld.org/dili/Pages/default.aspx). Observations by Dr. Hyman J. Zimmerman that “drug-induced hepatocellular jaundice is a serious lesion” with possible mortality formed a basis for developing a computer program to plot peak serum values for alanine aminotransferase (ALT) and total bilirubin (TBL) in an x–y log–log graph for all subjects enrolled in clinical trials. This program had the capability to show the time course of all liver tests for individuals who had both hepatocellular injury and reduced whole liver function, plus clinical narratives to diagnose the severity and most likely cause of the abnormalities. We called the program eDISH (for evaluation of Drug-Induced Serious Hepatotoxicity), and began in 2004 to use it to assess DILI in clinical trial subjects. From 2008, comments made by the presenters at the conferences about their slides and ensuing discussions have been added to the website. All this has raised awareness of the problem, and since 1997, the FDA has not had to withdraw a single drug because of post-marketing hepatotoxicity. Many issues still remain to be resolved; among the most controversial is the best method to estimate likelihood that a given liver injury was actually caused by the drug in question. On November 9, 2012, a workshop was convened to discuss the best practices for the assessment of drug-induced liver injury (DILI) in clinical trials.

Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors

Besides their role in the elucidation of pathogenic processes of medical and pharmacological nature, biomarkers can also be used to document specific toxicological events. Hepatic cells generated from human skin-derived precursors (hSKP-HPC) were previously shown to be a promising in vitro tool for the evaluation of drug-induced hepatotoxicity. In this study, their capacity to identify potential liver-specific biomarkers at the gene expression level was investigated with particular emphasis on acute liver failure (ALF). To this end, a set of potential ALF-specific biomarkers was established using clinically relevant liver samples obtained from patients suffering from hepatitis B-associated ALF. Subsequently, this data was compared to data obtained from primary human hepatocyte cultures and hSKP-HPC, both exposed to the ALF-inducing reference compound acetaminophen. It was found that both in vitro systems revealed a set of molecules that was previously identified in the ALF liver samples. Yet, only a limited number of molecules was common between both in vitro systems and the ALF liver samples. Each of the in vitro systems could be used independently to identify potential toxicity biomarkers related to ALF. It seems therefore more appropriate to combine primary human hepatocyte cultures with complementary in vitro models to efficiently screen out potential hepatotoxic compounds.

Salvianolic acid A, a matrix metalloproteinase-9 inhibitor of Salvia miltiorrhiza, attenuates aortic aneurysm formation in apolipoprotein E-deficient mice

Aortic aneurysm (AA) is a life-threatening vascular disease in defect of effective pharmaceutical therapy. Matrix metalloproteinase-9 (MMP-9) is implicated in the development of chronic vascular diseases including aneurysm, but the effective MMP-9 inhibitors are far from development. To develop new candidate for AA therapy, we evaluated the efficiency of salvianolic acid A (SalA), a novel MMP-9 inhibitor, on AA progression in a mouse model and characterized the mechanism of action. SalA is a water soluble compound of the herbal drug Rhizoma Salviae miltiorrhizae (Danshen) which in China is widely used for the treatment of hypertension, coronary artery diseases and myocardial infarction. MMPs activity was evaluated by enzyme kinetic analysis in vitro and in-gel gelatin zymography in vivo. SalA showed selectivity on gelatinase (MMP-2 and MMP-9) than on collagenase (MMP-8 and MMP-13) in vitro, and specificity on MMP-9 than MMP-2 in vivo. Aortic aneurysm was induced by angiotension II (AngII) in apolipoprotein E-deficient (ApoE−/−) mice. Aortic structure was evaluated by hematoxylin and eosin, picrosirius red, orein stain. Macrophage infiltration was detected by immunohistochemistry in vivo and transwell in vitro. Comparing with doxycycline (Dox), a well-known MMPs inhibitor, SalA showed similar efficiency against AA progression. SalA significantly decreased aortic diameter and aneurysm severity, ameliorated integrity of vascular structure, inhibited elastin fragmentation and macrophage infiltration. Furthermore, SalA showed greater safety than Dox based on hepatotoxicity evaluation. Our results demonstrated that SalA held great potential for AA therapy.

Nephrotoxicity and hepatotoxicity evaluation of Crocus sativus stigmas in neonates of nursing mice.

Crocus sativus, known as saffron crocus, is best known for the spice saffron. Saffron use spans more than 3500 years, however, its toxicity on neonates during lactation has not yet evaluated. This study was aimed to examine the acute toxicity of saffron on adult mice and its nephrotoxicity and hepatotoxicity on neonates of lactating mothers that used saffron during lactation. In this experimental study, following acute toxicity evaluation, 32 pregnant mice were randomly designated into four equal groups. Following delivery, the mothers of groups 1 to 4 were administered orally (by gavage) normal saline (control group), 500, 1000 or 2000 mg/kg/day of saffron for three weeks, respectively. The newborn's kidney and liver parameters were assessed at the end of the study for possible nephrotoxicity and hepatotoxicity evaluation. The kidney and liver tissue samples of newborns were histopathologically studied after staining with Hematoxylin & Eosin. Data were analyzed using ANOVA and Scheffe's tests Results: The LD50 value of saffron was calculated to be 4120&plusmn;556 mg/kg in mice. To evaluate lactating toxicity, saffron was administered orally to the mothers once daily for 21 days, after delivery, during lactating period. Saffron increased serum urea nitrogen (p< 0.05). Histological studies indicated that saffron did not have any toxic effect on liver, however, histopathology changes were seen in the kidney of neonates. From the results of present study, it might be concluded that saffron is a nearly safe spice, however, nursing mothers should avoid high doses of this spice.

Real-time imaging of oxidative and nitrosative stress in the liver of live animals for drug-toxicity testing

Current drug-safety assays for hepatotoxicity rely on biomarkers with low predictive power. The production of radical species, specifically reactive oxygen species (ROS) and reactive nitrogen species (RNS), has been proposed as an early unifying event linking the bioactivation of drugs to hepatotoxicity and as a more direct and mechanistic indicator of hepatotoxic potential. Here we present a nanosensor for rapid, real-time in vivo imaging of drug-induced ROS and RNS for direct evaluation of acute hepatotoxicity. By combining fluorescence resonance energy transfer (FRET) and chemiluminescence resonance energy transfer (CRET), our semiconducting polymer–based nanosensor simultaneously and differentially detects RNS and ROS using two optically independent channels. Drug-induced hepatotoxicity and its remediation are imaged longitudinally in mice following systemic challenge with acetaminophen or isoniazid. Dose-dependent ROS and RNS activity is detected in the liver within minutes of drug challenge, preceding histological changes, protein nitration and DNA double strand break induction.

An evaluation of hepatotoxicity in breast cancer patients receiving injection doxorubicin

Background:Hepatic dysfunction in the cancer unit has a significant impact on patient outcomes. The therapeutic application of anthracycline antibiotics are limited by side-effects mainly myelosuppression, chronic cardiotoxicity, and hepatotoxicity.Aim:To assess the risk of Hepatotoxicity in breast cancer patients receiving Inj. Doxorubicin.Subjects and Methods:The investigation was a prospective study that was conducted in cancer patients receiving Inj. Doxorubicin doses of 50 mg/m2, and 75 mg/m2 at a South Indian tertiary care hospital. Sample collection was carried out from pre-chemotherapy to 4th cycle. Serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), direct bilirubin and total bilirubin were assessed to determine hepatotoxicity. Data were analyzed using unpaired t-test, Pearson correlation using Graph-Pad Prism version 5.00 for Windows, Graph-Pad Software, San Diego, California, USA, www.graphpad.com.Results:Breast cancer patients comprised 37% (49/132) of the total female cancer patient population, of which 46 patients with a mean age of 46.6 (13.4) years were included and 30.4% (14/46) patients were developed hepatotoxicity. The mean standard deviation of SGOT, SGPT, direct bilirubin, total bilirubin in the pre-chemotherapy cycle to fourth chemotherapy cycle were found to be 21.97 (5.798) U/L and 181.3 (103.6) U/L, 23.17 (6.237) U/L and 147.6 (90.9) U/L, 0.1351 (0.1186) mg/dL and 0.5445 (0.4587) mg/dL, 0.3094 (1.346) mg/dL and 2.7163 (1.898) mg/dL simultaneously where P < 0.05 which were statistically significant.Conclusion:There exist a strong correlation between the use of Inj. Doxorubicin and risk for developing hepatotoxicity. The health-care professionals dealing with breast cancer patients need to have awareness for hepatotoxicity with the use of Inj. Doxorubicin therapy.

Risk of hepatotoxicity associated with fluoroquinolones: A national case–control safety study

Results of a pharmacoepidemiologic evaluation of fluoroquinolone-associated hepatotoxicity using national hospital admissions data on Veterans Affairs (VA) patients are reported. In a retrospective case-control study, all adults with a primary diagnosis of hepatotoxicity on admission to a VA facility during a 6.5-year period (January 2002-June 2008) were identified. After the exclusion of patients whose records indicated known causes of hepatotoxicity or a history of liver disease, a subgroup of 7,862 patients with exposure to fluoroquinolone antibiotics in the six months prior to hospital admission were matched with nonexposed controls (n = 45,512). Conditional logistic regression was used to assess the overall and drug-specific risks of hepatotoxicity in the case group, controlling for comorbidities, concomitant use of known hepatotoxic medications, and other variables. After adjusting for confounders, logistic regression analysis indicated a significantly higher overall risk of hepatotoxicity development among fluoroquinolone users relative to controls (odds ratio [OR], 1.20; 95% confidence interval [CI], 1.04-1.38). Drug-specific risk analyses focused on three fluoroquinolone agents (ciprofloxacin, levofloxacin, and moxifloxacin) indicated a significant association between ciprofloxacin use and an increased risk of hepatotoxicity (OR, 1.29; 95% CI, 1.05-1.58); when considered as independent variables, levofloxacin use and moxifloxacin use were not significantly associated with hepatotoxicity risk. The findings of a national VA safety study suggested an increased hepatotoxicity risk asssociated with fluoroquinolone exposure in the study population.

Evaluation of hepatotoxicity and clastogenicity of carbofuran in male Wistar rats

Carbofuran based pesticides have gained wide usage in Nigeria recently. Consequently, animals and human populations are exposed to them in the environment. Information on in vivo toxicity of carbofuran in experimental models is scanty. The present study therefore examined the hepatotoxicity and clastogenic effects of carbofuran in rats. Male Wistar rats were exposed to carbofuran (p.o) at 0–5mg/kg bw for 5weeks. Carbofuran induced significant (p<0.05) increase in the serum activity of gamma-glutamyltransferase when compared with the negative control, but not activity of serum alanine and aspartate aminotransferases. It also significantly (p<0.05) induced micronucleated polychromatic erythrocytes formation in the bone marrow as compared with the control. The level of induction is dose dependent in both cases. In addition, there was significant (p<0.05) higher number of hepatic cells in the cell/mm2 assay for the group treated with carbofuran. Histopathological analysis of liver samples from the treated groups revealed lesions ranging from general congestion (portal, central venous and sinusoidal), mild periportal cellular infiltration, diffused sinusoidal congestion and hepatic necrosis to severe congestion. Findings from this study suggest that carbofuran has clastogenic and hepatotoxic effects in rats. It therefore may constitute an environmental health risks in individuals so exposed.