Protective effect of genistein pre-treatment on paraquat hepatotoxicity in rats.

Paraquat (PQ), an herbicide widely used in agriculture, is considered a highly toxic compound. In hepatocytes, P-glycoprotein (P-gp/Abcb1) is a canalicular transporter involved in PQ extrusion from the cell. Previously, we demonstrated that genistein (GNT) induces P-gp in rat liver. In this study, the protective role of GNT pretreatment towards hepatic damage in a model of acute intoxication with PQ in rats, was investigated. Wistar rats were randomized in 4 groups: Control, GNT (5 mg/kg/day sc, 4 days), PQ (50 mg/kg/day ip, last day) and GNT+ PQ. Hepatic lipoperoxidation (LPO) was evaluated by the thiobarbituric acid reactive substances method. Hepatic levels of 4-hydroxynonenal protein adducts (4-HNEp-add) and glutathione-S-transferase alpha (GSTα) protein expression were evaluated by Western blotting. Hepatic glutathione levels and plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST) were also measured. Biliary excretion of PQ was studied in vivo and in isolated perfused liver. PQ was quantified by HPLC. PQ significantly increased AST and ALT activities, malondialdehyde and 4-HNEp-add levels, whereby pretreatment with GNT ameliorated this effect. PQ biliary excretion remained unchanged after treatments in both experimental models. Hepatic GSTα expression was augmented in GNT group. GNT pretreatment increased hepatic glutathione levels in PQ + GNT group. These results agree with the lower content of 4-HNEp-adds in GNT + PQ group respect to PQ group. Unexpectedly, increased activity of P-gp did not enhance PQ biliary excretion. Thus, GNT protective mechanism is likely through the induction of GSTα which results in increased 4-HNE metabolism before formation of protein adducts.

Aedes aegypti mosquito saliva ameliorates acetaminophen-induced liver injury in mice.

Acetaminophen (N-acetyl-p-aminophenol, APAP) overdose is the most common cause of drug-induced liver injury (DILI). Although the primary hepatic damage is induced by APAP-derived toxic intermediates resulting from cytochrome P450 metabolism, immune components also play an important role in DILI pathophysiology. Aedes aegypti saliva is a source of bioactive molecules with in vitro anti-inflammatory and immunomodulatory activities. However, evidences on the therapeutic use of Ae. aegypti salivary preparations in animal models of relevant clinical conditions are still scarce. Thus, the present study was designed to evaluate the protective role of Ae. aegypti saliva in a murine model of APAP-induced DILI. C57BL/6 mice were exposed to Ae. aegypti bites 2 hours after APAP overdose. Biochemical and immunological parameters were evaluated in blood and liver samples at different time points after APAP administration. Exposure to Ae. aegypti saliva attenuated liver damage, as demonstrated by reduced hepatic necrosis and serum levels of alanine aminotransferase in APAP-overdosed mice. The levels of hepatic CYP2E1, the major enzyme responsible for the bioactivation of APAP, were not changed in Ae. aegypti exposed animals, suggesting no effects in the generation of hepatotoxic metabolites. On the other hand, mice treated with Ae. aegypti saliva following APAP overdose presented lower serum concentration of TNF-α, IL-6, IL-1ß and IL-10, as well as reduced frequency of inflammatory cell populations in the liver, such as NKT cells, macrophages and dendritic cells. These findings show that Ae. aegypti saliva has bioactive molecules with therapeutic properties and may represent a prospective source of new compounds in the management of DILI-associated inflammatory disorders and, perhaps, many other inflammatory/autoimmune diseases.

Efeitos adversos às drogas antituberculose: hepatotoxicidade / Adverse effects to antituberculosis drugs: hepatotoxicity

Objetivo: Verificar a frequência de efeitos adversos em pacientes em uso de drogas antituberculose de primeira linha, além dos fatores de risco associados aos efeitos adversos e à hepatotoxicidade. Métodos: Estudo transversal, envolvendo 196 pacientes portadores de tuberculose em Maceió (AL), de agosto de 2017 a junho de 2018. Os efeitos adversos foram classificados de acordo com o Manual de Recomendações para Controle da Tuberculose de 2011, do Ministério da Saúde, em efeitos menores (queixas gastrintestinais, cutâneos, articulares e neurológicos) e maiores (psicose e hepatotoxicidade). Os fatores de risco avaliados foram: idade superior a 40 anos, etilismo, sexo feminino, anemia, doença hepática anterior, diabetes e infecção por HIV. Resultados: Foram observados efeitos adversos às drogas antituberculose em 85 pacientes (43,4%); destes, 40,8% eram menores e 8,2%, maiores. Os mais frequentes foram distúrbios gastrintestinais (25,5%) e cutâneos (15,3%). Identificaram-se como fatores de risco anemia, diabetes e doença hepática anterior. Hepatotoxicidade foi diagnosticada em 15 pacientes (10,6%), dos quais 80% eram sintomáticos, sendo fatores de risco doença hepática anterior e diabetes. Houve suspensão da terapia em todos os casos de hepatotoxicidade com modificação do esquema em 80% dos casos. Conclusão: Demonstrou-se frequência elevada de efeitos adversos às drogas antituberculose, associada à doença hepática anterior e ao diabetes. A hepatotoxicidade representou o efeito adverso mais grave, responsável pela suspensão e pela adequação do esquema terapêutico.

Objective: To determine the adverse effects frequency in patients on first-line antituberculosis drugs, as well as the risk factors associated with adverse effects and hepatotoxicity. Methods: Cross-sectional study, involving 196 tuberculosis patients in Maceió (AL), from August 2017 to June 2018. Adverse effects were classified according to the Manual de Recomendações para Controle da Tuberculose, of the Brazilian Health Ministry, in minor effects (gastrointestinal, cutaneous, articular, neurologic complaints) and major effects (psychosis and hepatotoxicity). The risk factors evaluated were age over 40 years, alcoholism, female sex, anemia, previous hepatic disease, diabetes, and infection by HIV. Results: Adverse effects to the antituberculosis drugs were observed in 85 patients (43.4%) and, among those, 40.8% were minor and 8.2% were major effects. The most frequent were gastrointestinal (25.5%) and skin (15.3%) disorders. Risk factors were identified as anemia, diabetes, and previous hepatic disease. Hepatotoxicity was diagnosed in 15 patients (10.6%), from which 80% were symptomatic, with previous hepatic disease and diabetes being the risk factors. Therapy was discontinued in all cases of hepatotoxicity with regimen modification in 80% of cases. Conclusion: An elevated frequency of adverse effects to antituberculosis drugs was demonstrated. Hepatotoxicity represented the most severe adverse effect, being responsible for the discontinuation and adaptation of the therapeutic regimen.

Hepatotoxicidade induzida por azatioprina em portadora da síndrome de Vogt-Koyanagi-Harada / Azathioprine-induced hepatotoxicity in a Vogt-Koyanagi-Harada syndrome patient

Este relato teve como objetivo apresentar um caso de hepatotoxicidade colestática induzida por azatioprina em portadora da síndrome de Vogt-Koyanagi-Harada. À admissão, apresentava icterícia +3/+4, acolia fecal e colúria, além de aumento de marcadores hepáticos, sendo compatível com síndrome colestática, cuja etiologia foi confirmada após exclusão de outras causas possíveis e retirada da azatioprina. A paciente evoluiu, após 1 semana de retirada do fármaco, com diurese livre de coloração menos escura e evacuação presente, sem acolia. Além disso, houve melhora nos exames que precederam a alta hospitalar

This report aimed at presenting a case of azathioprine-induced cholestatic hepatotoxicity in a patient with Vogt-Koyanagi-Harada syndrome. On admission, she presented with jaundice +3/+4, acholic feces, and choluria, as well as increased hepatic markers, all consistent with cholestatic syndrome, the etiology of which was confirmed after other possible causes were ruled out and azathioprine was discontinued. After 1 week of the drug discontinuation, the patient progressed with free diuresis of lighter color and defecation, with no acholia. In addition, tests performed before discharge were improved.

p-Chloro-diphenyl diselenide attenuates plasma lipid profile changes and hepatotoxicity induced by nonionic surfactant tyloxapol in rats.

Tyloxapol is a nonionic surfactant oligomer inductor of dyslipidemia, which in turn is a risk factor for liver damage. Selenium-based compounds have emerged as promising therapeutic candidates for treating different experimental disorders. This study investigated the effects of p-chloro-diphenyl diselenide (p-ClPhSe)2 on toxicity induced by Tyloxapol in rats. Plasma lipid profile, hepatic functionality and oxidative stress parameters were evaluated in adult male Wistar rats treated with (p-ClPhSe)2 (10 mg/kg; oral administration by gavage) for seven days and exposed to a single Tyloxapol injection (400 mg/kg; intraperitoneal route) 30 min after the last (p-ClPhSe)2 treatment. Tyloxapol exposure increased the plasma levels of total cholesterol, triacylglycerol, non-HDL-cholesterol and the calculated cardiac risk index (CRI). The plasma activities of alanine and aspartate aminotransferase (ALT and AST, liver function markers) were increased in rats exposed to Tyloxapol, which demonstrates a hepatic lipotoxicity. In the liver, reactive oxygen species (ROS) content was enhanced and the non-protein sulfhydryl (NPSH) levels were decreased by Tyloxapol. The data revealed that repeated treatment with (p-ClPhSe)2 reduced plasma lipid alterations and hepatotoxicity induced by Tyloxapol. Although (p-ClPhSe)2 did not reduce ROS levels increased by Tyloxapol, it increased NPSH content in the liver. Pearson's correlation coefficient revealed a positive relationship between the levels of hepatic NPSH and plasma HDL. HDL is known by eliciting antioxidant activity; therefore, the improvement in HDL function could be suggested as a therapeutic target. In conclusion, the results demonstrate the protective effects of (p-ClPhSe)2 on the hepatic lipotoxicity induced by Tyloxapol in rats.

Vanishing bile duct syndrome related to DILI and Hodgkin lymphoma overlap: A rare and severe case.

Vanishing bile duct syndrome is a rare acquired condition, characterized by progressive loss of intrahepatic bile ducts leading to ductopenia and cholestasis. It can be associated with infections, ischemia, drug adverse reactions, neoplasms, autoimmune disease, and allograft rejection. Prognosis is variable and depends on the etiology of bile duct injury. We report the case of a 25-year-old female with cholestatic hepatitis and concomitant intakes of hepatotoxic substances, such as garcinia, field horsetail, and ketoprofen. On suspicion of a drug-induced liver injury, the drugs were promptly withdrawn and ursodeoxycholic acid was started with initial clinical and laboratory improvement, and the patient was discharged from the hospital. One month later, she had a new increase in bilirubin levels and canalicular enzymes, requiring a liver biopsy that showed significant loss of intrahepatic bile ducts, which was compatible with vanishing bile duct syndrome. This was confirmed by using cytokeratin 19 on immunohistochemistry. There was subsequent lymph node enlargement in several chains, and relevant weight loss. Histological analysis of a cervical lymph node revealed nodular sclerosis-subtype classic Hodgkin lymphoma. In this setting, vanishing bile duct syndrome was related to Hodgkin lymphoma and a drug-induced liver injury overlap, leading to progressive cholestasis with a worse prognosis. The patient's response to chemotherapy was poor, requiring biological therapy with brentuximab vedotin. It is crucial for physicians to create a broad differential diagnosis in suspected vanishing bile duct syndrome patients, especially to rule out malignancies.

Protective Effect of Vitamin C on Triptolide-induced Acute Hepatotoxicity in Mice through mitigation of oxidative stress.

Triptolide, a purified diterpenoid from the herb Tripterygium wilfordii Hook.f., was widely used to treat many diseases. However, the hepatotoxicity of triptolide limited its clinical use. Research showed oxidative stress played an important role in triptolide-induced liver injury. To investigate the effect of vitamin C, which was one of the most effective antioxidants, on triptolide-induced hepatotoxicity and its potential mechanism in mice. In the present study, acute liver injury was induced by intraperitoneal injection of triptolide and vitamin C was orally administered. The results showed treatment with vitamin C prevented the triptolide-induced liver injury by reducing the levels of aspartate transaminase from 286.86 to 192.48 U/mL and alanine aminotransferase from 746.75 to 203.36 U/mL. Histopathological changes of liver corresponded to the same trend. Furthermore, vitamin C also protected the liver against triptolide-induced oxidative stress by inhibiting the generation of malondialdehyde (2.22 to 1.49 nmol/mgprot) and hydrogen peroxide (14.74 to 7.19 mmol/gprot) and restoring the level of total superoxide dismutase (24.32 to 42.55 U/mgprot) and glutathione (7.69 to 13.03 µg/mgprot). These results indicated that vitamin C could protect against triptolide-induced liver injury via reducing oxidative stress, and vitamin C may pose a significant health protection in the clinical use of triptolide.

Assessment of Serious Acute and Chronic Idiosyncratic Drug-Induced Liver Injury in Clinical Practice.

Drug-induced liver injury (DILI) is the leading cause of acute liver failure (ALF) in developed countries. The extremely variable phenotype of DILI, both in presentation and in severity, is one of the distinctive characteristics of the disease and one of the major challenges that hepatologists face when assessing hepatotoxicity cases. A new Hy's law that more accurately predicts the risk of ALF related to DILI has been proposed and validated. Other prognostic scoring algorithms for the early identification of DILI patients who may go on to develop ALF have been developed as it is of most clinical relevance to stratify patients for closer monitoring. Recent data indicate that acute DILI often presents a more prolonged resolution or evolves into chronicity at a higher frequency than other forms of acute liver injury. Risk factors for chronicity, specific phenotypes, and histological features are discussed in this study. Biomarkers to predict DILI outcome are in need.

Undue Elevation of Procalcitonin in Pediatric Paracetamol Intoxication is Not Explained by Liver Cell Injury Alone.

INTRODUCTION AND AIM: Procalcitonin is widely used as a biomarker to distinguish bacterial infections from other etiologies of systemic inflammation. Little is known about its value in acute liver injury resulting from intoxication with paracetamol. MATERIAL AND METHODS: We performed a single-center retrospective analysis of the procalcitonin level, liver synthesis, liver cell damage and renal function of patients admitted with paracetamol-induced liver injury to a tertiary care children's hospital. Children with acute liver failure due to other reasons without a bacterial or fungal infection served as the control group. Twelve patients with acute paracetamol intoxication and acute liver injury were compared with 29 patients with acute liver failure. RESULTS: The procalcitonin levels were higher in children with paracetamol intoxication than in patients with acute liver failure without paracetamol intoxication (median 24.8 (0.01-55.57) ng/mL vs. 1.36 (0.1-44.18) ng/mL; p < 0.005), although their liver and kidney functions were better and the liver cell injury was similar in both groups. Outcome analysis showed a trend towards better survival without transplantation in patients with paracetamol intoxication (10/12 vs. 15/29). Within each group, procalcitonin was significantly correlated with alanine aminotransferase and aspartate aminotransferase but was not correlated with the International Normalized Ratio or paracetamol blood levels in the paracetamol group. In conclusion, paracetamol intoxication leads to a marked increase in procalcitonin serum levels, which are significantly higher than those seen in acute liver failure. CONCLUSION: The underlying mechanism is neither caused by infection nor fully explained by liver cell death alone and remains to be determined.

Modulatory Effect of Dietary Inclusion of Aegle marmelos Fruits against Cisplatin - Induced Hepatotoxicity In Wistar Rats.

INTRODUCTION AND AIM: Aegle marmelos is an important traditional herbal medicine used in India. The dietary inclusion of the plant has never exposed earlier for its hepatoprotective activity. This study aimed to investigate the modulator efficacy of dietary inclusion of Aegle marmelos against Cisplatin - induced hepatotoxicity in Wistar albino rats. MATERIAL AND METHODS: Animals were divided into five different groups; Group I was given basal diets only, Group II was fed basal diets with Aegle marmelos in 4% concentration, while Group III was fed basal diets co-administered with Cisplatin. Group IV and V were administered diets containing 2 and 4% Aegle marmelos respectively, for 27 days prior to Cisplatin administration. Cisplatin was administered to the rats for 3 days leads to a reduction in the activities of the antioxidant enzymes like lipid peroxidation (LPO) and endogenous antioxidant systems such as reduced superoxide dismutase (SOD), glutathione (GSH) and catalase in liver homogenate caused to produce the impairment of hepatic functions. RESULTS: The administration of fruit part of Aegle marmelos to Wistar rats showed a significant fall in the elevated Lipid peroxidation, superoxide dismutase, glutathione and catalase concentration, moreover, it diminished the increased serum level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), acid phosphatase (ACP) and bilirubin. CONCLUSIONS: We can conclude that the hepatoprotective activity of Aegle marmelos was due to its antioxidant effect as evidenced by increasing activity of antioxidant enzymes with enhanced hepatic function and significantly changed the physiological parameters.

Noncholestatic acute hepatocellular injury following candesartan administration.

Arterial hypertension is a highly manageable disorder due to a variety of drugs available for its treatment. Since the late 1990s, angiotensin II receptor blockers have been widely prescribed, achieving appropriate control in patients' blood pressure. Few cases of serious adverse effects have been reported to date. Here, we present a case of acute hepatocellular injury secondary to candesartan administration. Further studies should be performed in patients who present with this adverse effect, in order to prevent more serious outcomes.

Autotransplantation of Spleen Mitigates Drug-Induced Liver Damage in Splenectomized Mice.

PURPOSE: The spleen presents numerous functions, including the production of immunoglobulins and blood filtration, removing microorganisms and cellular debris. The spleen also has anatomical and functional relationship with the liver, but there are few studies on this topic. The aim of this study was to assess the effect of splenectomy and autologous spleen transplantation on both filtering functions of spleen and acetaminophen-induced hepatotoxicity. MATERIALS AND METHODS: Fifty-two BALB/c mice were randomized into four groups: splenectomized; splenectomy and splenic autotransplantation in the greater omentum; sham operated control; and non-operated control. At day 7th, 14th, and 28th after surgery, splenic filtration was assessed by counting Howell-Jolly bodies (HJB) and pitted red cells (PIT). The animals received 400 mg/kg acetaminophen by gavage at day 28th and after 12 or 24 hours were euthanized for evaluation of splenic and hepatic morphology. RESULTS: The splenectomized group demonstrated reduced filtration of HJB and PIT in all analyzes, while the autotransplanted group developed progressive recovery of function after the 14th day. At day 28 after surgery the implants showed similar histology in comparison to normal spleen. Liver histology showed more intense centrilobular necrosis in splenectomized group in comparison to the others, suggesting a protective role of spleen in acetaminophen-induced liver injury. CONCLUSIONS: Splenic implants showed structural and functional recovery, demonstrating the ability of autologous implant to rescue filtering function of intact spleen. Furthermore, the integrity of splenic function appears to influence liver morphology, since the presence of the splenic implants mitigated the effects of chemically-induced liver damage.

Serum Acetaminophen Protein Adduct Concentrations in Pediatric Emergency Department Patients.

OBJECTIVES: Acetaminophen toxicity is a common cause of pediatric liver failure. The diagnosis may be limited by the short window of detection of acetaminophen in serum. Recently acetaminophen protein adducts (APAP-CYS) have been used as a biomarker with a longer duration of detection. The objective of this study was to describe the serum concentrations of APAP-CYS in pediatric patients with and without reported therapeutic acetaminophen exposure. METHODS: A cross-sectional study of children age 1 to <12 years presenting to a pediatric emergency department. Subjects were stratified by recent acetaminophen use and had serum APAP-CYS measured using LC/MS. RESULTS: One hundred patients were enrolled. All of the patients whose caregivers denied acetaminophen exposure had nondetectable APAP-CYS. Fifty-two percent of subjects who were reported to have taken acetaminophen in the preceding 2 weeks had detectable serum APAP-CYS. The APAP-CYS concentrations were positively correlated with higher overall dose and more recent ingestion. CONCLUSIONS: APAP-CYS is detectable in the majority of children taking acetaminophen and not detected in the majority of children who are not exposed to acetaminophen.

Albumin dialysis with MARS for the treatment of anabolic steroid-induced cholestasis.

 Background and aims. Steroid-related hepatotoxicity has become one of the most relevant causes of drug induced liver cholestasis. Some patients do not improve after standard medical treatment (SMT) and may therefore require other approaches, like extracorporeal liver support. MATERIAL AND METHODS: We report four cases of patients with pruritus, abnormal liver function tests and biopsy-proven anabolic steroid-induced cholestasis who were unresponsive to SMT. They underwent treatment with albumin dialysis (Molecular Adsorbent Recirculating System -MARS®-). A minimum of two MARS sessions were performed. RESULTS: After MARS® procedure, patients' symptoms improved, as well as liver function tests, thus avoiding liver transplantation. CONCLUSION: Albumin dialysis appears as a valuable therapeutic option for the management of anabolic steroid-induced cholestasis in patients that are unresponsive to SMT.

Early initiation of MARS® dialysis in Amanita phalloides-induced acute liver injury prevents liver transplantation.

 Amanita phalloides is the most relevant mushroom intoxication leading to acute liver failure. The two principal groups of toxins, the amatoxins and the phallotoxins, are small oligopeptides highly resistant to chemical and physical influences. The amatoxins inhibit eukaryotic RNA polymerase II causing transcription arrest affecting mainly metabolically highly active cells like hepatocytes and renal cells. The clinically most characteristic symptom is a 6-40 h lag phase before onset of gastrointestinal symptoms and the rapid progression of acute liver failure leading to multi-organ failure and death within a week if left untreated. Extracorporeal albumin dialysis (ECAD) was reported to improve patient's outcome or facilitate bridging to transplantation. In our tertiary center, out of nine intoxicated individuals from five non-related families six patients presented with acute liver injury; all of them were treated with ECAD using the MARS® system. Four of them were listed on admission for high urgency liver transplantation. In addition to standard medical treatment for Amanita intoxication we initiated ECAD once patients were admitted to our center. Overall 16 dialysis sessions were performed. All patients survived with full native liver recovery without the need for transplantation. ECAD was well tolerated; no severe adverse events were reported during treatment. Coagulopathy resolved within days in all patients, and acute kidney injury in all but one individual. In conclusion, ECAD is highly effective in treating intoxication with Amanita phalloides. Based on these experiences we suggest early initiation and repeated sessions depending on response to ECAD with the chance of avoiding liver transplantation.

Hematological and hepatic alterations in Brazilian population heavily exposed to organochlorine pesticides.

The aim of this study was to investigate the frequency of hematological and hepatic alterations and possible association with serum levels of beta-hexachlorocyclohexane (beta-HCH), p,p'-DDE, and hexachlorobenzene (HCB) among residents in an area heavily contaminated with organochlorine (OC) pesticides. A cross-sectional study was conducted in 415 male and 432 female residents aged >14 years. Serum samples were collected and analyzed for OC pesticides concentrations and biochemical parameters. Frequencies of hematological and hepatic alterations were calculated for each gender. Association between beta-HCH, p,p'-DDE (1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene), and HCB levels and presence of alterations was determined by logistic regression stratified by gender and controlling for confounders. Highest frequencies were observed for eosinophilia (23% men and 18% women), low hemoglobin (12% men and 15% women), and low erythrocyte count (12% men). High levels of bilirubin, glutamic-oxaloacetic transaminase (GOT), and glutamic-pyruvic transaminase (GPT) were observed, respectively, in 10, 11, and 12% of men and <10% of women. Gamma-glutamyl transferase (GGT) was elevated in 26 and 25% of males and females, respectively. Multivariate analysis revealed associations between eosinophilia and beta-HCH in men (OR = 1.06, 95%CI = 1.01-1.12) and women (OR = 1.05, 96%CI = 0.99-1.11), p,p'-DDE in men (OR = 1.03, 95%CI = 0.99-1.06) and women (OR = 1.02, 95%CI = 0.99-1.06), and HCB in women (OR = 1.54, 95%IC = 0.85-4.45). Beta-HCH was found to be associated with increased risk of elevated bilirubin in females (OR = 1.18, 95%CI = 1.07-1.29) and males (OR = 4.21, 95%CI = 1.87-9.47 for fourth vs. first quintile). Thus, OC pesticides may exert adverse effects on hematopoietic tissue and liver in populations chronically exposed to high levels of these compounds.

Significance of alanine aminotransferase levels in patients admitted for cocaine intoxication.

BACKGROUND: Experimental studies in animal models and case reports in humans have described the hepatotoxic potential of cocaine. However, there are few data regarding the clinical and laboratory characteristics of patients admitted for cocaine intoxication, particularly regarding the status of the liver enzymes. GOAL: To investigate the significance of alanine aminotransferase (ALT) levels in individuals hospitalized for acute cocaine intoxication. METHODS: Retrospective study with standardized chart review that included patients admitted between January 2003 and December 2010. Bivariate analyses were used to investigate factors associated with ALT above the upper tertile according to gender. Cases of marked ALT elevation were described in detail. RESULTS: Ninety-three patients were included (79% men, mean age of 27.73±9.97 y). ALT above the upper tertile was associated with higher aspartate aminotransferase (AST), creatine phosphokinase, creatinine, and international normalized ratio. Higher levels of ALT were also related to acute renal failure and death. Five subjects had severe ALT elevation during follow-up and all had evidence of hepatocellular dysfunction (jaundice, prolonged prothrombin time with or without hepatic encephalopathy), rhabdomyolysis, and acute renal failure. AST/ALT ratio <2 was present in 2 subjects with severe ALT elevation at admission, but AST/ALT ratio >2 was observed in 3 cases with evidence of progression to acute liver injury. CONCLUSIONS: In acute cocaine intoxication, higher ALT levels were associated with evidence of muscle damage, progression to acute renal failure, and death. Severe liver damage was observed in 5% of the sample and was associated with rhabdomyolysis and renal failure in all cases.

Differences in antioxidant activities of outdoor- and indoor-cultivated Agaricus brasiliensis, and protective effects against carbon tetrachloride-induced acute hepatic injury in mice.

BACKGROUND: Agaricus brasiliensis (A. brasiliensis) is a medicinal mushroom that exerts various pharmacological actions. We previously demonstrated that different cultivation conditions altered the activity of the polyphenol-related enzymes from this mushroom. However, the influence of cultivation conditions on the antioxidant activity of the fruiting bodies remains unclear. Therefore, in this study we compared the antioxidative effects of fruiting bodies of A. brasiliensis cultivated outdoors and indoors. In addition, we assessed whether different cultivation methods affected the hepatoprotective effects against CCl4-induced liver injury. METHODS: We assessed the antioxidative effects of mushrooms cultivated in open-air or indoors using the DPPH radical-scavenging assay. Furthermore, we prepared experimental feeds containing outdoor- or indoor-cultivated A. brasiliensis. Acute liver injury was induced by CCl4 injection in mice that consumed feed containing outdoor- or indoor-cultivated A. brasiliensis. The hepatoprotective effects of these mushrooms were then evaluated by monitoring the reduction in the circulating levels of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase. The significance of the differences between the means was assessed using Student's t-test. Finally, histopathological analysis of liver was performed. RESULTS: In the DPPH assay, the antioxidant activity of outdoor-cultivated A. brasiliensis was higher than that of indoor-cultivated mushroom. Moreover, in the mouse model of CCl4-induced hepatitis, the oral administration of outdoor-cultivated A. brasiliensis reduced liver damage significantly, but indoor-cultivated mushrooms failed to inhibit hepatitis. The hepatoprotective effects of outdoor-cultivated A. brasiliensis were observed even when ingestion commenced only 1 day before CCl4 injection, and these effects were not affected by excessive heat treatment. CONCLUSIONS: Outdoor cultivation significantly enhanced the antioxidative activity of A. brasiliensis fruiting bodies. In addition, outdoor-cultivated A. brasiliensis was more effective at protecting against CCl4-induced liver injury in mice than mushrooms grown in a greenhouse.