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Modulation of the benzene metabolite hydroquinone induced toxicity: evidence for an important role of fau

Inayat-Hussain SH, Ibrahim HA, Siew EL, Rajab NF, Chan KM, G T Williams, et al.

Chem Biol Interact, 2010 Mar 19;184(1-2):310-2.
PMID: 20025857 DOI: 10.1016/j.cbi.2009.12.009
Mutagenic and clastogenic characterization of poststerilized poly(3-hydroxybutyrate-co-4-hydroxybutyrate) copolymer biosynthesized by Delftia acidovorans

Siew EL, Rajab NF, Osman AB, Sudesh K, Inayat-Hussain SH

J Biomed Mater Res A, 2009 Dec;91(3):786-94.
PMID: 19051306 DOI: 10.1002/jbm.a.32290

Polyhydroxyalkanoates (PHA) are naturally occurring biopolyesters that have great potential in the medical field. However, the leachables resulting from sterilization process of the biomaterials may exert toxic effect including genetic damage. Here, we demonstrate that although gamma-irradiation of poly(3-hydroxybutyrate-co-50 mol % 4-hydroxybutyrate) [P(3HB-co-4HB)] did not cause any change in the morphology by scanning electron microscopy, there was a significant degradation of this copolymer where the molecular weight was reduced by 37% after sterilization indicating the generation of leachables. Therefore, further investigation on the ability of the extract of this poststerilized copolymer to induce mutagenic effect was performed using Ames test (S. typhimurium strains TA1535 and TA1537) and umu test (S. typhimurium strain TA1535/pSK1002). Additionally, the capability of the extract to induce clastogenic effect was determined using Chinese hamster lung V79 fibroblast cells. Our results showed that with and without the presence of S9 metabolic activation, no mutagenic effects were observed in both Ames and umu tests when treated with P(3HB-co-4HB) extract. Similarly, treatment of P(3HB-co-4HB) extract in V79 fibroblast cells showed no significant production of micronuclei when compared with the positive control (Mitomycin C). Together, these results indicate that leachables of poststerilized P(3HB-co-4HB) cause no mutagenic and clastogenic effects.
Prioritization of reproductive toxicants in unconventional oil and gas operations using a multi-country regulatory data-driven hazard assessment

Inayat-Hussain SH, Fukumura M, Muiz Aziz A, Jin CM, Jin LW, Garcia-Milian R, et al.

Environ Int, 2018 08;117:348-358.
PMID: 29793188 DOI: 10.1016/j.envint.2018.05.010

BACKGROUND: Recent trends have witnessed the global growth of unconventional oil and gas (UOG) production. Epidemiologic studies have suggested associations between proximity to UOG operations with increased adverse birth outcomes and cancer, though specific potential etiologic agents have not yet been identified. To perform effective risk assessment of chemicals used in UOG production, the first step of hazard identification followed by prioritization specifically for reproductive toxicity, carcinogenicity and mutagenicity is crucial in an evidence-based risk assessment approach. To date, there is no single hazard classification list based on the United Nations Globally Harmonized System (GHS), with countries applying the GHS standards to generate their own chemical hazard classification lists. A current challenge for chemical prioritization, particularly for a multi-national industry, is inconsistent hazard classification which may result in misjudgment of the potential public health risks. We present a novel approach for hazard identification followed by prioritization of reproductive toxicants found in UOG operations using publicly available regulatory databases.
METHODS: GHS classification for reproductive toxicity of 157 UOG-related chemicals identified as potential reproductive or developmental toxicants in a previous publication was assessed using eleven governmental regulatory agency databases. If there was discordance in classifications across agencies, the most stringent classification was assigned. Chemicals in the category of known or presumed human reproductive toxicants were further evaluated for carcinogenicity and germ cell mutagenicity based on government classifications. A scoring system was utilized to assign numerical values for reproductive health, cancer and germ cell mutation hazard endpoints. Using a Cytoscape analysis, both qualitative and quantitative results were presented visually to readily identify high priority UOG chemicals with evidence of multiple adverse effects.
RESULTS: We observed substantial inconsistencies in classification among the 11 databases. By adopting the most stringent classification within and across countries, 43 chemicals were classified as known or presumed human reproductive toxicants (GHS Category 1), while 31 chemicals were classified as suspected human reproductive toxicants (GHS Category 2). The 43 reproductive toxicants were further subjected to analysis for carcinogenic and mutagenic properties. Calculated hazard scores and Cytoscape visualization yielded several high priority chemicals including potassium dichromate, cadmium, benzene and ethylene oxide.
CONCLUSIONS: Our findings reveal diverging GHS classification outcomes for UOG chemicals across regulatory agencies. Adoption of the most stringent classification with application of hazard scores provides a useful approach to prioritize reproductive toxicants in UOG and other industries for exposure assessments and selection of safer alternatives.
Protection of hydroquinone-induced apoptosis by downregulation of Fau is mediated by NQO1

Siew EL, Chan KM, Williams GT, Ross D, Inayat-Hussain SH

Free Radic. Biol. Med., 2012 Oct 15;53(8):1616-24.
PMID: 22687461 DOI: 10.1016/j.freeradbiomed.2012.05.046

The Fau gene (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV)-associated ubiquitously expressed gene) was identified as a potential tumor suppressor gene using a forward genetics approach. Downregulation of Fau by overexpression of its reverse sequence has been shown to inhibit apoptosis induced by DNA-damaging agents. To address a potential role of Fau in benzene toxicity, we investigated the apoptotic effects of hydroquinone (HQ), a major benzene metabolite, in W7.2 mouse thymoma cells transfected with either a plasmid construct expressing the antisense sequence of Fau (rfau) or the empty vector (pcDNA3.1) as a control. HQ induced apoptosis via increased production of reactive oxygen species and DNA damage, measured using dihydroethidine (HE) staining and alkaline Comet assay, respectively, in W7.2 pcDNA3.1 cells. In contrast, when Fau was downregulated by the antisense sequence in W7.2 rfau cells, HQ treatment did not cause DNA damage and oxidative stress and these cells were markedly more resistant to HQ-induced apoptosis. Further investigation revealed that there was an upregulation of NAD(P)H: quinone oxidoreductase 1 (NQO1), a detoxification enzyme for benzene-derived quinones, in W7.2 rfau cells. Compromising cellular NQO1 by use of a specific mechanism-based inhibitor (MAC 220) and NQO1 siRNA resensitized W7.2 rfau cells to HQ-induced apoptosis. Silencing of Fau in W7.2 wild-type cells resulted in increased levels of NQO1, confirming that downregulation of Fau results in NQO1 upregulation which protects against HQ-induced apoptosis.
Fulltext RACK-1 overexpression protects against goniothalamin-induced cell death

Inayat-Hussain SH, Wong LT, Chan KM, Rajab NF, Din LB, Harun R, et al.

Toxicol Lett, 2009 Dec 15;191(2-3):118-22.
PMID: 19698770 DOI: 10.1016/j.toxlet.2009.08.012

Goniothalamin, a styryllactone, has been shown to induce cytotoxicity via apoptosis in several tumor cell lines. In this study, we have examined the potential role of several genes, which were stably transfected into T-cell lines and which regulate apoptosis in different ways, on goniothalamin-induced cell death. Overexpression of full-length receptor for activated protein C-kinase 1 (RACK-1) and pc3n3, which up-regulates endogenous RACK-1, in both Jurkat and W7.2 T cells resulted in inhibition of goniothalamin-induced cell death as assessed by MTT and clonogenic assays. However, overexpression of rFau (antisense sequence to Finkel-Biskis-Reilly murine sarcoma virus-associated ubiquitously expressed gene) in W7.2 cells did not confer resistance to goniothalamin-induced cell death. Etoposide, a clinically used cytotoxic agent, was equipotent in causing cytotoxicity in all the stable transfectants. Assessment of DNA damage by Comet assay revealed goniothalamin-induced DNA strand breaks as early as 1 h in vector control but this effect was inhibited in RACK-1 and pc3n3 stably transfected W7.2 cells. This data demonstrate that RACK-1 plays a crucial role in regulating cell death signalling pathways induced by goniothalamin.
Styryl-lactone goniothalamin inhibits TNF-α-induced NF-κB activation

Orlikova B, Schumacher M, Juncker T, Yan CC, Inayat-Hussain SH, Hajjouli S, et al.

Food Chem Toxicol, 2013 Sep;59:572-8.
PMID: 23845509 DOI: 10.1016/j.fct.2013.06.051

(R)-(+)-Goniothalamin (GTN), a styryl-lactone isolated from the medicinal plant Goniothalamus macrophyllus, exhibits pharmacological activities including cytotoxic and anti-inflammatory effects. In this study, GTN modulated TNF-α induced NF-κB activation. GTN concentrations up to 20 μM showed low cytotoxic effects in K562 chronic myelogenous leukemia and in Jurkat T cells. Importantly, at these concentrations, no cytotoxicity was observed in healthy peripheral blood mononuclear cells. Our results confirmed that GTN inhibited tumor necrosis factor-α (TNF-α)-induced NF-κB activation in Jurkat and K562 leukemia cells at concentrations as low as 5 μM as shown by reporter gene assays and western blots. Moreover, GTN down-regulated translocation of the p50/p65 heterodimer to the nucleus, prevented binding of NF-κB to its DNA response element and reduced TNF-α-activated interleukin-8 (IL-8) expression. In conclusion, GTN inhibits TNF-α-induced NF-κB activation at non-apoptogenic concentrations in different leukemia cell models without presenting toxicity towards healthy blood cells underlining the anti-leukemic potential of this natural compound.
The Malaysian Society of Toxicology: from establishment to evolution, a promising future!

Kamaludin NF, Kamarulzaman F, Abdullah R, Chan KM, Inayat-Hussain SH

Genes Environ, 2023 Dec 11;45(1):34.
PMID: 38072940 DOI: 10.1186/s41021-023-00290-5

The Malaysian Society of Toxicology (MySOT), founded in 2010, emerged as a response to the growing need for a collective and interdisciplinary effort to study the effects of substances on human health, and the environment. By fostering collaboration between toxicologists, researchers, regulators, industry experts, and various relevant subject matter experts, MySOT has played a vital role in generating knowledge and promoting safety to safeguard both human and environmental well-being. Within the 13 years since its establishment, MySOT has made substantial progress in the advancement of toxicology in Malaysia. Over the years, MySOT has supported many initiatives, including organizing conferences, seminars, and workshops in which experts from various fields present their research, discuss emerging trends, and propose strategies to reduce toxic substance exposure risk. The society has also been actively involved in the broader landscape of toxicology research and policy influence in Malaysia. MySOT shoulders the responsibility of conveying accurate information and educating the public about health risks associated with toxic substances. Therefore, the society aims to collaborate with governmental organizations, professional bodies, and international toxicology organizations to share ideas, resources, and expertise. MySOT seeks to gather toxicological experts in the region and significantly contribute to a safer and healthier community, therefore supporting the United Nations Sustainable Development Goals (SDGs), by being actively involved with all of its stakeholders, both local and international.
The pyranoxanthone inophyllin A induces oxidative stress mediated-apoptosis in Jurkat T lymphoblastic leukemia cells

Chan KM, Hamzah R, Rahaman AA, Jong VY, Khong HY, Rajab NF, et al.

Food Chem Toxicol, 2012 Aug;50(8):2916-22.
PMID: 22613213 DOI: 10.1016/j.fct.2012.04.048

Inophyllin A (INO-A), a pyranoxanthone isolated from the roots of Calophyllum inophyllum represents a new xanthone with potential chemotherapeutic activity. In this study, the molecular mechanism of INO-A-induced cell death was investigated in Jurkat T lymphoblastic leukemia cells. Assessment of phosphatidylserine exposure confirmed apoptosis as the primary mode of cell death in INO-A-treated Jurkat cells. INO-A treatment for only 30 min resulted in a significant increase of tail moment which suggests that DNA damage is an early apoptotic signal. Further flow cytometric assessment of the superoxide anion level confirmed that INO-A induced DNA damage was mediated with a concomitant generation of reactive oxygen species (ROS). Investigation on the thiols revealed an early decrease of free thiols in 30 min after 50 μM INO-A treatment. Using tetramethylrhodamine ethyl ester, a potentiometric dye, the loss of mitochondrial membrane potential (MPP) was observed in INO-A-treated cells as early as 30 min. The INO-A-induced apoptosis progressed with the simultaneous activation of caspases-2 and -9 which then led to the processing of caspase-3. Taken together, these data demonstrate that INO-A induced early oxidative stress, DNA damage and loss of MMP which subsequently led to the activation of an intrinsic pathway of apoptosis in Jurkat cells.
Toxicity of tetramethylammonium hydroxide to aquatic organisms and its synergistic action with potassium iodide

Mori IC, Arias-Barreiro CR, Koutsaftis A, Ogo A, Kawano T, Yoshizuka K, et al.

Chemosphere, 2015 Feb;120:299-304.
PMID: 25151133 DOI: 10.1016/j.chemosphere.2014.07.011

The aquatic ecotoxicity of chemicals involved in the manufacturing process of thin film transistor liquid crystal displays was assessed with a battery of four selected acute toxicity bioassays. We focused on tetramethylammonium hydroxide (TMAH, CAS No. 75-59-2), a widely utilized etchant. The toxicity of TMAH was low when tested in the 72 h-algal growth inhibition test (Pseudokirchneriellia subcapitata, EC50=360 mg L(-1)) and the Microtox® test (Vibrio fischeri, IC50=6.4 g L(-1)). In contrast, the 24h-microcrustacean immobilization and the 96 h-fish mortality tests showed relatively higher toxicity (Daphnia magna, EC50=32 mg L(-1) and Oryzias latipes, LC50=154 mg L(-1)). Isobologram and mixture toxicity index analyses revealed apparent synergism of the mixture of TMAH and potassium iodide when examined with the D. magna immobilization test. The synergistic action was unique to iodide over other halide salts i.e. fluoride, chloride and bromide. Quaternary ammonium ions with longer alkyl chains such as tetraethylammonium and tetrabutylammonium were more toxic than TMAH in the D. magna immobilization test.