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Drug and chemical poisoning admissions at a teaching hospital in Malaysia

Ab Rahman AF

Hum Exp Toxicol, 2002 Jul;21(7):377-81.
PMID: 12269700

A retrospective review of medical records was carried out to determine the pattern of drug and chemical poisoning cases admitted to a teaching hospital in Malaysia. Medical records of patients admitted during the period January 1987 to December 1995 were reviewed. They accounted for 0.2% of total admissions during the period. While all ages were represented, there was predominance of children, which showed little change throughout the nine-year period. Of all cases of poisoning, 77.8% were unintentional, 12.6% intentional and 9.6% were undetermined. Kerosene, pesticides and medicinal substances remained the common agents associated with poisoning. A significant number of patients sought treatment elsewhere before being admitted to the hospital. Of those who came directly to the hospital, many were presented late in the course of their poisoning. Only seven patients died and none were children. This study supports the need for greater emphasis on prevention of poisoning in children and among farmers in the state.
Evaluate the impact of hospital types on the availability of antidotes for the management of acute toxic exposures and poisonings in Malaysia

Al-Sohaim SI, Awang R, Zyoud SH, Rashid SM, Hashim S

Hum Exp Toxicol, 2012 Mar;31(3):274-81.
PMID: 21478291 DOI: 10.1177/0960327111405861

The availability of antidotes may be considered essential and lifesaving in the management of certain poisonings. Surveys carried out in a number of countries have demonstrated inadequate availability of a variety of poisoning antidotes.
S-Allyl cysteine alleviates inflammation by modulating the expression of NF-κB during chromium (VI)-induced hepatotoxicity in rats

Anandasadagopan SK, Sundaramoorthy C, Pandurangan AK, Nagarajan V, Srinivasan K, Ganapasam S

Hum Exp Toxicol, 2017 Nov;36(11):1186-1200.
PMID: 28988497 DOI: 10.1177/0960327116680275

Hexavalent chromium (Cr (VI)) is a common environmental pollutant. Cr (VI) exposure can lead to severe damage to the liver, but the preventive measures to diminish Cr (VI)-induced hepatotoxicity need further study. S-allyl cysteine (SAC) is a constituent of garlic ( Allium sativum) and has many beneficial effects to humans and rodents. In this study, we intended to analyze the mechanistic role of SAC during Cr (VI)-induced hepatotoxicity. Male Wistar albino rats were induced with 17 mg/kg body weight to damage the liver. The Cr (VI)-induced rats were treated with 100 mg/kg body weight of SAC as an optimum dosage to treat hepatotoxicity. We observed that the levels of oxidants, lipid peroxidation and hydroxyl radical (OH(•)) were increased, and enzymatic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were found to be decreased in Cr (VI)-induced rats. While treated with SAC, the levels of oxidants were decreased and enzymatic antioxidants were significantly ( p < 0.05) increased. Lysosomal enzyme activities were increased in Cr (VI)-induced rats and on treatment with SAC, the activities were significantly decreased. The expressions of nuclear factor-kappa B (p65-NF-κB), tumor necrosis factor α (TNF-α), and inducible nitric oxide synthase (iNOS) were increased during induction with Cr (VI). Subsequent administration of SAC to animals showed a decrease in the expressions of NF-κB, TNF-α, and iNOS. Results obtained from this study clearly demonstrated that SAC protects the liver cells from the Cr (VI)-induced free radical damage.
Analysis of lead content in herbal preparations in Malaysia

Ang HH, Lee EL, Matsumoto K

Hum Exp Toxicol, 2003 Aug;22(8):445-51.
PMID: 12948085 DOI: 10.1191/0960327103ht382oa

In Malaysia, the phase 3 registration for traditional medicines was implemented on 1 January 1992 under the Control of Drugs and Cosmetics Regulation 1984, emphasizing quality, efficacy and safety (including the detection of the presence of heavy metals) in all pharmaceutical dosage forms of traditional medicine preparations. Therefore, a total of 100 products in various pharmaceutical dosage forms of a herbal preparation, were analysed for lead content using atomic absorption spectrophotometer. Results showed that 8% (eight products) possessed 10.64-20.72 ppm of lead, and therefore, do not comply with the quality requirement for traditional medicines in Malaysia. One of these products, M-Tongkat Ali (exhibited 10.64 +/-0.37 ppm of lead), was in fact already registered with the DCA Malaysia. The rest, Sukarno Tongkat Ali, Eurycoma Madu, Super Pill Tongkat Ali, Force Pill Tongkat Ali, Tender Pill Tongkat Ali, Super Pill Tongkat Ali Plus and Great Pill Tongkat Ali Plus have not registered with the DCA Malaysia and exhibited 12.24-20.72 ppm of lead. Although this study showed that only 92% of the products complied with the quality requirement for traditional medicines in Malaysia, however, they cannot be assumed safe from lead contamination because of batch-to-batch inconsistency.
Diallyl sulphide, a component of garlic, abrogates ferric nitrilotriacetate-induced oxidative stress and renal damage in rats

Ansar S, Iqbal M, AlJameil N

Hum Exp Toxicol, 2014 Dec;33(12):1209-16.
PMID: 24596035 DOI: 10.1177/0960327114524237

Ferric nitrilotriacetate (Fe-NTA) induces tissue necrosis as a result of lipid peroxidation (LPO) and oxidative damage that leads to high incidence of renal carcinomas. The present study was undertaken to evaluate the effect of diallyl sulphide (DAS) against Fe-NTA-induced nephrotoxicity. A total of 30 healthy male rats were randomly divided into 5 groups of 6 rats each: (1) control, (2) DAS (200 mg kg(-1)), (3) Fe-NTA (9 g Fe kg(-1)), (4) DAS (100 mg kg(-1)) + Fe-NTA (9 mg Fe kg(-1)) and (5) DAS (200 mg kg(-1)) + Fe-NTA (9 mg Fe kg(-1)). Fe-NTA + DAS-treated groups were given DAS for a period of 1 week before Fe-NTA administration. The intraperitoneal administration of Fe-NTA enhanced blood urea nitrogen and creatinine levels with reduction in levels of antioxidant enzymes. However, significant restoration of depleted renal glutathione and its dependent enzymes (glutathione reductase and glutathione-S-transferase) was observed in DAS pretreated groups. DAS also attenuated Fe-NTA-induced increase in LPO, hydrogen peroxide generation and protein carbonyl formation (p < 0.05). The results indicate that DAS may be beneficial in ameliorating the Fe-NTA-induced renal oxidative damage in rats.
Protective effect of diallylsulphide against mercuric chloride-induced hepatic injury in rats

Ansar S, Iqbal M

Hum Exp Toxicol, 2016 Dec;35(12):1305-1311.
PMID: 26825963

The present study was undertaken to evaluate the effect of diallylsulphide (DAS) against mercuric chloride (HgCl2)-induced oxidative stress in rat livers. Rats were randomly divided into four groups of six rats each and exposed to HgCl2 (50 mg/kg/body weight (b.w.)) intraperitoneally and/or DAS (200 mg/kg/b.w.) by gavage. HgCl2 administration enhanced alanine aminotransferase (AST) and aspartate aminotransferase (ALT) levels (p < 0.05) with reduction in the levels of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). However, treatment with DAS markedly attenuated HgCl2-induced biochemical alterations in liver and serum transaminases (AST and ALT; p < 0.05). Further, biochemical results were confirmed by histopathological changes as compared to HgCl2-intoxicated rats. Histopathology of liver also showed that administration of DAS significantly reduced the damage generated by HgCl2 The present study suggests that DAS shows antioxidant activity and plays a protective role against mercury-induced oxidative damage in the rat livers.
Antioxidant and nephroprotective potential of butylated hydroxyanisole against ferric nitrilotriacetate-induced oxidative stress and early tumor events

Ansar S, Iqbal M

Hum Exp Toxicol, 2016 Apr;35(4):448-53.
PMID: 26078281 DOI: 10.1177/0960327115591378

The present study was aimed to study protective effect of butylated hydroxyanisole (BHA), a phenolic antioxidant used in foods on ferric nitrilotriacetate (Fe-NTA)-induced nephrotoxicity. Male albino rats of Wistar strain (4-6 weeks old) weighing 125-150 g were used in this study. Animals were given a single dose of Fe-NTA (9 mg kg(-1) body weight) after treatment with BHA (1 and 2 mg animal(-1) day(-1)). Fe-NTA treatment enhanced ornithine decarboxylase (ODC) activity to 5.3-fold, and [(3)H]-thymidine incorporation in DNA to 2.5-fold in kidney compared with the corresponding saline-treated control, whereas glutathione (GSH) levels and the activities of antioxidant enzymes decreased to a range of 2- to 2.5-fold in kidney. These changes were reversed significantly in animals receiving a pretreatment of BHA. The enhanced ODC activity and DNA synthesis showed a reduction to 2.12-fold and 1.15-fold, respectively, at a higher dose of 2 mg BHA day(-1) animal(-1), compared with the Fe-NTA-treated groups. Pretreatment with BHA prior to Fe-NTA treatment increased GSH and the activities of antioxidant enzymes to a range of 1.5- to 2-fold in kidney. The results indicate that BHA suppresses Fe-NTA-induced nephrotoxicity in male Wistar rats.
Amelioration of ferric nitrilotriacetate-induced hepatotoxicity in Wistar rats by diallylsulfide

Ansar S, Iqbal M

Hum Exp Toxicol, 2016 Mar;35(3):259-66.
PMID: 25904316 DOI: 10.1177/0960327115583362

Garlic contains diallylsulfide (DAS) and other structurally related compounds that are widely believed to be active agents in preventing cancer. This study shows the effect of DAS (a phenolic antioxidant used in foods, cosmetics, and pharmaceutical products) on ferric nitrilotriacetate (Fe-NTA)-induced hepatotoxicity in rats. Male albino rats of Wistar strain weighing 125-150 g were given a single dose of Fe-NTA (9 mg kg(-1) body weight, intraperitoneally) after 1 week of treatment with 100 and 200 mg kg(-1) DAS in corn oil respectively administered through the gavage. Fe-NTA administration led to 2.5-fold increase in the values of both alanine transaminase and aspartate aminotransferase, respectively, and 3.2-fold increase in the activity of lactate dehydrogenase, microsomal lipid peroxidation to approximately 2.0-fold compared to saline-treated control. The activities of glutathione (GSH) and other antioxidant enzymes decreased to a range of 2.2-2.5-fold. These changes were reversed significantly (p < 0.001) in animals receiving a pretreatment of DAS. DAS protected against hepatic lipid peroxidation, hydrogen peroxide generation, preserved GSH levels, and GSH metabolizing enzymes to 60-80% as compared to Fe-NTA alone-treated group. Present data suggest that DAS can ameliorate the toxic effects of Fe-NTA and suppress oxidant-induced tissue injury and hepatotoxicity in rats.
Genetic, epigenetic, and lineage-directed mechanisms in benzene-induced malignancies and hematotoxicity targeting hematopoietic stem cells niche

Dewi R, Hamid ZA, Rajab NF, Shuib S, Razak SA

Hum Exp Toxicol, 2020 May;39(5):577-595.
PMID: 31884827 DOI: 10.1177/0960327119895570

Benzene is a known hematotoxic and leukemogenic agent with hematopoietic stem cells (HSCs) niche being the potential target. Occupational and environmental exposure to benzene has been linked to the incidences of hematological disorders and malignancies. Previous studies have shown that benzene may act via multiple modes of action targeting HSCs niche, which include induction of chromosomal and micro RNA aberrations, leading to genetic and epigenetic modification of stem cells and probable carcinogenesis. However, understanding the mechanism linking benzene to the HSCs niche dysregulation is challenging due to complexity of its microenvironment. The niche is known to comprise of cell populations accounted for HSCs and their committed progenitors of lymphoid, erythroid, and myeloid lineages. Thus, it is fundamental to address novel approaches via lineage-directed strategy to elucidate precise mechanism involved in benzene-induced toxicity targeting HSCs and progenitors of different lineages. Here, we review the key genetic and epigenetic factors that mediate hematotoxicological effects by benzene and its metabolites in targeting HSCs niche. Overall, the use of combined genetic, epigenetic, and lineage-directed strategies targeting the HSCs niche is fundamental to uncover the key mechanisms in benzene-induced hematological disorders and malignancies.
Factors associated with adult poisoning in northern Malaysia: a case-control study

Fathelrahman AI, Ab Rahman AF, Zain ZM, Tengku MA

Hum Exp Toxicol, 2006 Apr;25(4):167-73.
PMID: 16696291

Data on adult risk factors associated with drug or chemical poisonings in Malaysia are scarce. The objective of the study was to identify possible risk factors associated with adult admissions to the Penang General Hospital (PGH) due to chemical poisoning and/or drug overdose. The present study was a case-control study, conducted over 18 weeks. One hundred acutely poisoned adult patients admitted to PGH during the period from September 2003 to February 2004 were considered as cases. Two hundred patients admitted to the same medical wards for other illnesses, during the same period, were matched for age and gender with the poisoned cases and thus selected as controls. McNemar test and binary logistic were used for univariate analysis and logistic regression analysis for multivariate analyses. The odds ratio (OR) and its 95% confidence interval (95% CI) were calculated for each predictor variable. Positive histories of psychiatric illness and previous poisoning, problems in boy/girl friend relationships, family problems, marital problems, Indian ethnicity, Chinese ethnicity, living in rented houses and living in a household with less than five people were significant risk factors associated with adult admissions due to poisoning.
Guggulsterone, a farnesoid X receptor antagonist lowers plasma trimethylamine-N-oxide levels: An evidence from in vitro and in vivo studies

Gautam A, Paudel YN, Abidin S, Bhandari U

Hum Exp Toxicol, 2019 Mar;38(3):356-370.
PMID: 30526076 DOI: 10.1177/0960327118817862

The current study investigated the role of guggulsterone (GS), a farnesoid X receptor antagonist, in the choline metabolism and its trimethylamine (TMA)/flavin monooxygenases/trimethylamine-N-oxide (TMAO) inhibiting potential in a series of in vitro and in vivo studies as determined by high-performance liquid chromatography (HPLC), mass spectroscopy (MS), and liquid chromatography (LC)-MS techniques. Atherosclerosis (AS) was successfully induced in a group of experimental animals fed with 2% choline diet for 6 weeks. Serum lipid profiles such as total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol were measured. Pro-inflammatory cytokines levels, markers for a hepatic injury, and oxidative stress markers were assessed. Interestingly, GS reduced the level of TMA/TMAO in both in vitro and in vivo studies as demonstrated by the peaks obtained from HPLC, MS, and LC-MS. Furthermore, GS exhibited cardioprotective and antihyperlipidemic effects as evidenced by the attenuation of levels of several serum lipid profiles and different atherogenic risk predictor indexes. GS also prevented hepatic injury by successfully restoring the levels of hepatic injury biomarkers to normal. Similarly, GS inhibited the production of pro-inflammatory cytokines levels, as well as GS, enhanced antioxidant capacity, and reduced lipid peroxidation. Histopathological study of aortic sections demonstrated that GS maintained the normal architecture in AS-induced rats. On the basis of results obtained from current investigation, we suggest that GS might have a great therapeutic potential for the treatment of AS.
Cytotoxic and antioxidant effects of methoxylated stilbene analogues on HepG2 hepatoma and Chang liver cells: Implications for structure activity relationship

Hasiah AH, Ghazali AR, Weber JF, Velu S, Thomas NF, Inayat Hussain SH

Hum Exp Toxicol, 2011 Feb;30(2):138-44.
PMID: 20385705 DOI: 10.1177/0960327110368739

Stilbenes possess a variety of biological activities including chemopreventive activity. This study was conducted to evaluate the structural activity relationships of six methoxylated stilbene analogues with respect to their cytotoxic effects and antioxidant activities on HepG2 hepatoma and Chang liver cells. The cytotoxic and total antioxidant activities of six stilbene analogues were determined by MTT and Ferric Reducing Antioxidant Power (FRAP) assays, respectively. We found that the cis-methoxylated stilbene: (Z)-3,4,4'-trimethoxystilbene was the most potent and selective antiproliferative agent (IC₅₀ 89 µM) in HepG2 cells. For the total antioxidant activity, compounds possessing hydroxyl groups at the 4' position namely (E)-3-methoxy-4'-hydroxystilbene, (E)-3,5-dimethoxy-4'-hydroxystilbene (pterostilbene), (E)-4-methoxy-4'-hydroxystilbene showed the highest antioxidant activity. Structure activity relationship studies of these compounds demonstrated that the cytotoxic effect and antioxidant activities of the tested compounds in this study were structurally dependent.
Antioxidant potential of Cymbopogon citratus extract: alleviation of carbon tetrachloride-induced hepatic oxidative stress and toxicity

Koh PH, Mokhtar RA, Iqbal M

Hum Exp Toxicol, 2012 Jan;31(1):81-91.
PMID: 21508074 DOI: 10.1177/0960327111407226

This study was aimed to evaluate the effect of Cymbopogon citratus against carbon tetrachloride (CCl(4))-mediated hepatic oxidative damage in rats. Rats were administrated with C. citratus extract (100, 200 and 300 mg/kg b.w.) for 14 days before the challenge of CCl(4) (1.2 ml/kg b.w. p.o) on 13th and 14th days. Hepatic damage was evaluated by employing serum biochemical parameters (alanine aminotransferase-ALT, aspartate aminotransferase-AST and lactate dehydrogenase-LDH), malondialdehye (MDA) level, reduced GSH and antioxidant enzymes (catalase: CAT, glutathione peroxidase: GPX, quinone reductase: QR, glutathione S-transferase: GST, glutathione reductase: GR, glucose-6-phosphate dehyrogenase: G6PD). In addition, CCl(4)-mediated hepatic damage was further evaluated by histopathological examination. However, most of these changes were alleviated by prophylactic treatment of animals with C. citratus dose dependently (p < 0.05). The protection was further evident through decreased histopathological alterations in liver. The results of the present study indicated that the hepatoprotective effect of C. citratus might be ascribable to its antioxidant and free radical scavenging property.
Cytochrome P450 4B1 (CYP4B1) as a target in cancer treatment

Lim S, Alshagga M, Ong CE, Chieng JY, Pan Y

Hum Exp Toxicol, 2020 Jun;39(6):785-796.
PMID: 32054340 DOI: 10.1177/0960327120905959

Cytochrome P450 4B1 (CYP4B1) plays crucial roles in biotransforming of xenobiotics. Its predominant extrahepatic expression has been associated with certain tissue-specific toxicities. However, the expressions of CYP4B1 in various cancers and hence their potential roles in cancer development were inclusive. In this work, existing knowledge on expression and regulation of CYP4B1 gene and protein, catalysis of CYP4B1, association of CYP4B1 with cancers, contradicting findings about human CYP4B1 activities as well as the employing CYP4B1 in suicide gene approach for cancer treatment were reviewed. To date, it appears that there is a wide spectrum of tissue distribution of CYP4B1 with lungs as the predominant sites. Several nuclear receptors are possibly responsible for regulating its gene expression. The involvement of CYP4B1 in cancer was considered via activation of procarcinogens and neovascularization. However, human CYP4B1 was found to be inactive due to a substitution of proline with serine at position 427. Suicide gene approach combining reengineered CYP4B1 and prodrug 4-ipomeanol (4-IPO) has shown a promising potential for targeted cancer therapy. Further studies should focus on the verification of human CYP4B1 catalytic activities. More compounds with similar structure as 4-IPO should be tested to identify more alternative agents for the suicide gene approach in cancer treatment.
Insight into potential mechanisms of hypobaric hypoxia-induced learning and memory deficit - Lessons from rat studies

Qaid E, Zakaria R, Sulaiman SF, Yusof NM, Shafin N, Othman Z, et al.

Hum Exp Toxicol, 2017 Dec;36(12):1315-1325.
PMID: 28111974 DOI: 10.1177/0960327116689714

Impairment of memory is one of the most frequently reported symptoms during sudden hypoxia exposure in human. Cortical atrophy has been linked to the impaired memory function and is suggested to occur with chronic high-altitude exposure. However, the precise molecular mechanism(s) of hypoxia-induced memory impairment remains an enigma. In this work, we review hypoxia-induced learning and memory deficit in human and rat studies. Based on data from rat studies using different protocols of continuous hypoxia, we try to elicit potential mechanisms of hypobaric hypoxia-induced memory deficit.
Hepatoprotective potential of glyceryl trinitrate against chemically induced oxidative stress and hepatic injury in rats

Rahman A, Vasenwala SM, Iqbal M

Hum Exp Toxicol, 2017 Aug;36(8):785-794.
PMID: 27758841 DOI: 10.1177/0960327116665675

Glyceryl trinitrate (GTN) has been used widely as a potent vasodilator to treat heart conditions, such as angina pectoris and chronic heart failure. This study aims to elucidate the effect of exogenous nitric oxide (NO) administration, using GTN, on carbon tetrachloride (CCl4)-induced oxidative stress and liver injury in rats. The results obtained demonstrated that NO generated by the administration of GTN affords protection against CCl4-induced oxidative stress and liver injury. Administration of CCl4resulted in a significant ( p < 0.001) increase in lipid peroxidation and tissue damage markers (aspartate and alanine transaminase and lactate dehydrogenase) release in serum. Parallel to these changes, CCl4also caused downregulation of antioxidant enzymes including glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST), and several fold induction in γ-glutamyl transpeptidase (GGT) activity. Subsequent administration of GTN resulted in significant ( p < 0.001) recovery of GSH-metabolizing enzymes in a dose-dependent manner. Further, administration of NO inhibitor, NG-nitro-l-arginine methyl ester (l-NAME), exacerbated CCl4-induced oxidative tissue injury. Overall, the study suggests that GTN might suppress oxidant-induced tissue injury and hepatotoxicity in rats.
Profile of poisoning admissions in Malaysia

Rajasuriar R, Awang R, Hashim SB, Rahmat HR

Hum Exp Toxicol, 2007 Feb;26(2):73-81.
PMID: 17370864

We retrospectively reviewed poisoning admissions to all government health facilities from 1999 to 2001, in an effort to expand our current knowledge on poisoning in Malaysia to a level that better reflects a nationwide burden. There were 21 714 admissions reported with 779 deaths. The case-fatality rate was 35.88/1000 admissions. The majority of admissions (89.7%) and deaths (98.9%) occurred in adults. Some 55.1% of all admissions were female, mostly involving pharmaceutical agents. Male poisoning admissions were more often due to chemical substances. The prevalence of poisoning and death was highest among Indians compared to all other races in Malaysia. Overall, the majority of poisoning admissions were due to pharmaceutical agents, with agents classified as non-opioid analgesics, anti-pyretics and anti-rheumatics the most common. Pesticides accounted for the largest number of fatalities. It was also the commonest substance reported in cases of intentional self-harm. Most cases of poisoning admissions occurred due to accidental exposure (47%), followed by cases of intentional self-harm (20.7%). Overall, this study has managed to contribute substantial additional information regarding the epidemiology of poisoning in Malaysia, highlighting important issues, such as the rampant poisonings involving pesticides and analgesics, as well as the high prevalence of poisoning among Indians in Malaysia.
Tocotrienol preserves ovarian function in cyclophosphamide therapy

Saleh HS, Omar E, Froemming GR, Said RM

Hum Exp Toxicol, 2015 Oct;34(10):946-52.
PMID: 25585998 DOI: 10.1177/0960327114564793

Cyclophosphamide (CPA) chemotherapy leads to ovarian failure and infertility. Tocotrienol (T3) is an antioxidant and anti-inflammatory agent. The role of T3 in ovarian protection throughout chemotherapy remains unclear.
Decline in sperm count in European men during the past 50 years

Sengupta P, Borges E, Dutta S, Krajewska-Kulak E

Hum Exp Toxicol, 2018 Mar;37(3):247-255.
PMID: 28413887 DOI: 10.1177/0960327117703690

PURPOSE: To investigate whether the sperm concentration of European men is deteriorating over the past 50 years of time.
MATERIALS AND METHODS: We analysed the data published in English language articles in the past 50 years in altering sperm concentration in European men.
RESULTS: A time-dependent decline of sperm concentration ( r = -0.307, p = 0.02) in the last 50 years and an overall 32.5% decrease in mean sperm concentration was noted.
CONCLUSION: This comprehensive, evidence-based meta-analysis concisely presents the evidence of decreased sperm concentration in European male over the past 50 years to serve the scientific research zone related to male reproductive health.
Hepatotoxicity induced by antifungal drugs itraconazole and fluconazole in rats: a comparative in vivo study

Somchit N, Norshahida AR, Hasiah AH, Zuraini A, Sulaiman MR, Noordin MM

Hum Exp Toxicol, 2004 Nov;23(11):519-25.
PMID: 15625777

Itraconazole and fluconazole are oral antifungal drugs, which have a wide spectrum antifungal activity and better efficacy than the older drugs. However, both drugs have been associated with hepatotoxicity in susceptible patients. The mechanism of antifungal drug-induced hepatotoxicity is largely unknown. Therefore, the aim of this present study was to investigate and compare the hepatotoxicity induced by these drugs in vivo. Rats were treated intraperitoneally with itraconazole or fluconazole either single (0, 10, 100 and 200 mg/kg) or subchronic (0, 10, 50 and 100 mg/kg per day for 14 days) doses. Plasma and liver samples were taken at the end of the study. A statistically significant and dose dependent increase of plasma alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities were detected in the subchronic itraconazole-treated group. In addition, dose-dependent hepatocellular necrosis, degeneration of periacinar and mizonal hepatocytes, bile duct hyperplasia and biliary cirrhosis and giant cell granuloma were observed histologically in the same group. Interestingly, fluconazole treated rats had no significant increase in transaminases for both single and subchronic groups. In the subchronic fluconazole treated rats, only mild degenerative changes of centrilobular hepatocytes were observed. These results demonstrated that itraconazole was a more potent hepatotoxicant than fluconazole in vivo in rats.

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