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Displaying publications 21 - 31 of 31 in total

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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.
Itraconazole- and fluconazole-induced toxicity in rat hepatocytes: a comparative in vitro study

Somchit N, Hassim SM, Samsudin SH

Hum Exp Toxicol, 2002 Jan;21(1):43-8.
PMID: 12046723

This current study was to investigate the in vitro cytotoxicity of rat hepatocytes induced by the antifungal drugs, itraconazole and fluconazole. Both antifungal drugs caused dose-dependent cytotoxicity. In vitro incubation of hepatocytes with itraconazole revealed significantly higher lactate dehydrogenase (LDH) leakage when compared to fluconazole. Phenobarbital pretreated hepatocytes contained significantly higher total cytochrome P450 content than the control hepatocytes. P450 content was reduced approximately 30% for both types of hepatocytes after 6 hours incubation. Interestingly, cytotoxicity of itraconazole was reduced significantly by phenobarbital pretreatment. Phenobarbital did not have any effect on the cytotoxicity induced by fluconazole. These results demonstrate the in vitro toxicity of hepatocytes induced by itraconazole and fluconazole that were expressed in a dose- and time-dependent manner. Phenobarbital plays a role in the cytoprotection of hepatocytes to itraconazole-induced but not fluconazole-induced cytotoxicity in vitro.
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.
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.
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.
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.
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.
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.
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.
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.
Fulltext Kaempferol ameliorates palmitate-induced lipid accumulation in HepG2 cells through activation of the Nrf2 signaling pathway

Zhao L, Yang L, Ahmad K

Hum Exp Toxicol, 2023;42:9603271221146780.
PMID: 36607234 DOI: 10.1177/09603271221146780

OBJECTIVES: Kaempferol (KMF), has beneficial effects against hepatic lipid accumulation. In this study, we aimed to investigate molecular mechanism underlying the protective effect of KMF on lipid accumulation.
METHODS: HepG2 cells were treated with different concentrations of KMF and 0.5 mM palmitate (PA) for 24 h. The mRNA and protein levels of genes involved in lipid metabolism were evaluated using real-time PCR and western blot. The expression of Nrf2 was silenced using siRNA.
RESULTS: Data indicated that KMF (20 μM) reversed PA-induced increased triglyceride (TG) levels and total lipid content. These effects were accompanied by down-regulation of the mRNA and protein levels of lipogenic genes (FAS, ACC and SREBP1), and up-regulation of genes related to fatty acid oxidation (CPT-1, HADHα and PPARα). Kaempferol significantly decreased the levels of the oxidative stress markers (ROS and MDA) and enhanced the activities of antioxidant enzymes SOD and GPx in PA-challenged cells. Luciferase analysis showed that KMF increased the transactivation of Nrf2 in hepatocytes. The results also revealed that KMF-mediated activation of Nrf2 target genes was suppressed by Nrf2 siRNA. Furthermore, Nrf2 siRNA abolished the KMF-induced reduction in ROS and MDA levels in PA treated cells. In addition, the inhibitory effect of KMF on TG levels and the mRNA and protein levels of FAS, ACC and SREPB-1 were significantly abolished by Nrf2 inhibition. Nrf2 inhibition also suppressed the KMF-induced activation of genes involved in β oxidation (CPT-1 and PPAR-α).
CONCLUSION: The results suggest that KMF protects HepG2 cells from PA-induced lipid accumulation via activation of the Nrf2 signaling pathway.

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