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The effects of Andrographis paniculata (Burm.f.) Nees extract and diterpenoids on the CYP450 isoforms' activities, a review of possible herb-drug interaction risks

Tan ML, Lim LE

Drug Chem Toxicol, 2015;38(3):241-53.
PMID: 25156015 DOI: 10.3109/01480545.2014.947504

Andrographis paniculata (Burm.f.) Nees is a popular medicinal plant and its components are used in various traditional product preparations. However, its herb-drug interactions risks remain unclear. This review specifically discusses the various published studies carried out to evaluate the effects of Andrographis paniculata (Burm.f.) Nees plant extracts and diterpenoids on the CYP450 metabolic enzyme and if the plant components pose a possible herb-drug interaction risk. Unfortunately, the current data are insufficient to indicate if the extracts or diterpenoids can be labeled as in vitro CYP1A2, CYP2C9 or CYP3A4 inhibitors. A complete CYP inhibition assay utilizing human liver microsomes and the derivation of relevant parameters to predict herb-drug interaction risks may be necessary for these isoforms. However, based on the current studies, none of the extracts and diterpenoids exhibited CYP450 induction activity in human hepatocytes or human-derived cell lines. It is crucial that a well-defined experimental design is needed to make a meaningful herb-drug interaction prediction.
Mutagenic and antimutagenic assessment of methanol leaf extract of Myristica fragrans (Houtt.) using in vitro and in vivo genetic assays

Akinboro A, Mohamed KB, Asmawi MZ, Othman AS, Ying TH, Maidin SM

Drug Chem Toxicol, 2012 Oct;35(4):412-22.
PMID: 22149219 DOI: 10.3109/01480545.2011.638300

The role of diets in causing cancers necessitates the ongoing search for natural antimutagens of promising anticancer therapeutics. This study determined the potential anticancer efficacy of the leaf extract of Myristica fragrans (Houtt.). Methanol leaf extract of M. fragrans (Houtt.) alone was screened for mutagenicity in the bacterial reverse mutation (Ames) test, using the Salmonella typhimurium TA100 strain, the Allium cepa, and the mouse in vivo bone marrow micronucleus tests. The antimutagenicity of this extract against benzo[a]pyrene- and cyclophosphamide-induced mutations was evaluated. An antioxidant test on the extract was performed with 2,2-diphenyl-1-picrylhydrazyl, using butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) as the standards, whereas its phytochemicals were elucidated by following the gas chromatography/mass spectrometry protocol. In S. typhimurium (TA100), the mutagenicity ratio at 200,500 and 1,000 µg/well was >2. Cell division in the A. cepa root tips and mouse bone marrow was significantly (P ≤ 0.05) inhibited at 2,000 and 4,000 mg/kg, whereas the observed chromosomal aberrations and micronucleated polychromatic erythrocytes were non-dose-related and were insignificantly (P ≥ 0.05) different from the negative control. Inhibition of benzo[a]pyrene- and cyclophosphamide-induced mutagenicity by this extract was above 40%. Half-maximal inhibitory concentration of the extract in the antioxidant test was lower than that of BHA and BHT. Phytochemical compounds, possessing antioxidant activity, may be responsible for the observed effects, suggesting a strong antimutagenic activity of the MeOH leaf extract of M. fragrans, a necessary characteristic of a promising anticancer agent.
Lack of hepato- and nephrotoxicity induced by antifungal drug voriconazole in laboratory rats

Somchit N, Chung JH, Yaacob A, Ahmad Z, Zakaria ZA, Kadir AA

Drug Chem Toxicol, 2012 Jul;35(3):304-9.
PMID: 22288423 DOI: 10.3109/01480545.2011.614619

Voriconazole is a new, potent broad-spectrum triazole systemic antifungal drug, a second-generation azole antifungal that is increasing in popularity, especially for the treatment of invasive aspergillosis and fluconazole-resistant invasive Candida infections. However, it is also known to induce hepatotoxicity clinically. The aim of this study was to investigate the hepatotoxicity and nephrotoxicity potential of voriconazole in vivo in rats. Forty rats were treated intraperitoneally with voriconazole as single (0, 10, l00, and 200 mg/kg) or repeated (0, 10, 50, and l00 mg/kg per day for 14 days) doses. Venous blood was collected for the repeated-dose group on days 1 and 14. Rats were sacrificed 24 hours after the last dose. Body weight, liver weight, and kidney weight of rats were recorded. Livers and kidneys samples were taken for histological and transmission electron microscopy (TEM) analysis. Results revealed that voriconazole had no effects on serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphotase, gamma glutamyl transpeptidase, blood urea nitrogen, and creatinine for both the single- and repeated-dose groups. However, histologically, in the repeated 50- and 100-mg/kg voriconazole-treated rats, mild focal inflammation was observed. Under TEM, only small changes in the 100 mg/kg/day group were revealed. These results collectively demonstrated that voriconazole did not induce significant hepatotoxicity and nephrotoxicity, even at very high doses.
Nitric oxide (NO), citrulline-NO cycle enzymes, glutamine synthetase, and oxidative status in kainic acid-mediated excitotoxicity in rat brain

Swamy M, Sirajudeen KN, Chandran G

Drug Chem Toxicol, 2009;32(4):326-31.
PMID: 19793024 DOI: 10.1080/01480540903130641

Neuronal excitation, involving the excitatory glutamate receptors, is recognized as an important underlying mechanism in neurodegenerative disorders. To understand their role in excitotoxicity, the nitric oxide synthase (NOS), argininosuccinate synthetase (AS), argininosuccinate lyase (AL), glutamine synthetase (GS), and arginase activities, along with the concentration of nitrate/nitrite, thiobarbituric acid-reactive substances (TBARS), and total antioxidant status (TAS), were estimated in the cerebral cortex, cerebellum, and brain stem of rats subjected to kainic acid-mediated excitotoxicity. The results of this study clearly demonstrated the increased production of NO by increased activity of NOS. The increased activities of AS and AL suggest the increased and effective recycling of citrulline to arginine in excitotoxicity, making NO production more effective and contributing to its toxic effects. The decreased activity of GS may favor the prolonged availability of glutamic acid, causing excitotoxicity, leading to neuronal damage. The increased formation of TBARS and decreased TAS indicate the presence of oxidative stress in excitotoxicity.
Involvement of phenobarbital and SKF 525A in the hepatotoxicity of antifungal drugs itraconazole and fluconazole in rats

Somchit N, Wong CW, Zuraini A, Ahmad Bustamam A, Hasiah AH, Khairi HM, et al.

Drug Chem Toxicol, 2006;29(3):237-53.
PMID: 16777703

Itraconazole and fluconazole are potent wide spectrum antifungal drugs. Both of these drugs induce hepatotoxicity clinically. The mechanism underlying the hepatotoxicity is unknown. The purpose of this study was to investigate the role of phenobarbital (PB), an inducer of cytochrome P450 (CYP), and SKF 525A, an inhibitor of CYP, in the mechanism of hepatotoxicity induced by these two drugs in vivo. Rats were pretreated with PB (75 mg/kg for 4 days) prior to itraconazole or fluconazole dosing (20 and 200 mg/kg for 4 days). In the inhibition study, for 4 consecutive days, rats were pretreated with SKF 525A (50 mg/kg) or saline followed by itraconazole or fluconazole (20 and 200 mg/kg) Dose-dependent increases in plasma alanine aminotransferase (ALT), gamma-glutamyl transferase (gamma-GT), and alkaline phosphatase (ALP) activities and in liver weight were detected in rats receiving itraconazole treatment. Interestingly, pretreatment with PB prior to itraconazole reduced the ALT and gamma-GT activities and the liver weight of rats. No changes were observed in rats treated with fluconazole. Pretreatment with SKF 525A induced more severe hepatotoxicity for both itraconazole and fluconazole. CYP 3A activity was inhibited dose-dependently by itraconazole treatment. Itraconazole had no effects on the activity of CYP 1A and 2E. Fluconazole potently inhibited all three isoenzymes of CYP. PB plays a role in hepatoprotection to itraconazole-induced but not fluconazole-induced hepatotoxicity. SKF 525A enhanced the hepatotoxicity of both antifungal drugs in vivo. Therefore, it can be concluded that inhibition of CYP may play a key role in the mechanism of hepatotoxicity induced by itraconazole and fluconazole.
Mutagenicity and preclinical safety assessment of the aqueous extract of Clinacanthus nutans leaves

Farsi E, Esmailli K, Shafaei A, Moradi Khaniabadi P, Al Hindi B, Khadeer Ahamed MB, et al.

Drug Chem Toxicol, 2016 Oct;39(4):461-73.
PMID: 27033971 DOI: 10.3109/01480545.2016.1157810

CONTEXT: Clinacanthus nutans (CN) is used traditionally for treating various illnesses. Robust safety data to support its use is lacking.
OBJECTIVE: To evaluate the adverse effects of aqueous extract of CN leaves (AECNL).
MATERIALS AND METHODS: The oral toxicity of the AECNL was tested following Organisation for Economic Co-operation and Development (OECD) guidelines. Mutagenicity (Ames test) of AECNL was evaluated using TA98 and TA100 Salmonella typhimurium strains.
RESULTS: No mortality or morbidity was found in the animals upon single and repeated dose administration. However, significant body weight loss was observed at 2000 mg/kg during sub-chronic (90 d) exposure. In addition, increased eosinophil at 500 mg/kg and decreased serum alkaline phosphatase levels at 2000 mg/kg were observed in male rats. Variations in glucose and lipid profiles in treated groups were also observed compared to control. Ames test revealed no evidence of mutagenic or carcinogenic effects at 500 μg/well of AECNL.
CONCLUSION: The median lethal dose (LD50) of the AECNL is >5000 mg/kg and the no-observed-adverse-effect level is identified to be greater than 2000 mg/kg/day in 90-d study.
Amiodarone-induced phospholipidosis: an in vivo [14C]-acetate uptake study in rat

Sirajudeen KN, Gurumoorthy P, Devaraj H, Devaraj SN

Drug Chem Toxicol, 2002 Aug;25(3):247-54.
PMID: 12173246

Amiodarone (AD), a potent antiarrhythmic drug, is often associated with several adverse effects. It is shown to accumulate phospholipids in various tissues, and the impaired catabolism of phospholipids has been implicated in AD-induced phospholipidosis. The synthesis of phospholipids in tissues has not been dealt with. Hence, the incorporation of [14C]-acetate into phospholipids has been studied to understand the AD-induced phospholipidosis in lung and liver. A significant increase in lung and liver phospholipids was observed after 21 and 28 days of AD (175 mg/kg body weight/day) treatment. In the lung and liver, the incorporation of [14C]-acetate into all phospholipid fractions was elevated, while in the lung mitochondria phosphatidylcholine, phosphatidyl ethanolamine and the cardiolipin levels were significantly increased. The results indicate that, in addition to the impaired catabolism of phospholipid, AD treatment resulted in increased phospholipid synthesis.
An electrochemical sensor for the determination of tartrazine based on CHIT/GO/MWCNTs/AuNPs composite film modified glassy carbon electrode

Rovina K, Siddiquee S, Md Shaarani S

Drug Chem Toxicol, 2021 Sep;44(5):447-457.
PMID: 31020858 DOI: 10.1080/01480545.2019.1601210

A novel nanocomposite film of chitosan/graphene oxide (CHIT/GO)/multi-walled carbon nanotubes (MWCNTs)/gold nanoparticles (AuNPs) was applied to fabricate glassy carbon electrode (CHIT/GO/MWCNTs/AuNPs/GCE) for the determination of Tartrazine (TZ), synthetic dyes in food products. The electrochemical sensors found it to be highly sensitive by combining the signal amplification properties of GO and the excellent electronic and antifouling properties of MWCNTs. The CHIT/GO/MWCNTs/AuNPs/GCE exhibited as superior electron transfer materials and possesses intercalation properties which provide synergistic influence on the increment of the current signals. The optimum conditions were found at pH 7, 30 s, and 0.3 Vs-1. The modified GCE obtained with a linear response ranging from 10 to 100 mg mL-1 (r2 = 0.99037) with a sensitivity of 0.018 μA μM-1. The limit of detection (LOD) and quantification obtained were 1.45 and 4.83 mg mL-1, respectively. The determination of TZ in spiked samples was reliable with recovery percentage from 94.52 to 109.0%. The developed sensor successfully tested in the determination of TZ analyte in commercial candy, jelly, and soft drinks with acceptable results.
Neuroprotective effects of Foeniculum vulgare seeds extract on lead-induced neurotoxicity in mice brain

Bhatti S, Ali Shah SA, Ahmed T, Zahid S

Drug Chem Toxicol, 2018 Oct;41(4):399-407.
PMID: 29742941 DOI: 10.1080/01480545.2018.1459669

The present study investigates the neuroprotective effects of Foeniculum vulgare seeds in a lead (Pb)-induced brain neurotoxicity mice model. The dried seeds extract of Foeniculum vulgare was prepared with different concentrations of organic solvents (ethanol, methanol, n-hexane). The in vitro antioxidant activity of Foeniculum vulgare seed extracts was assessed through DPPH assay and the chemical composition of the extracts was determined by high-resolution 1H NMR spectroscopy. The age-matched male Balb/c mice (divided into 9 groups) were administered with 0.1% Pb and 75% and 100% ethanol extracts of Foeniculum vulgare seeds at a dose of 200 mg/kg/day and 20 mg/kg/day. The maximum antioxidant activity was found for 75% ethanol extract, followed by 100% ethanol extract. Gene expression levels of oxidative stress markers (SOD1 and Prdx6) and the three isoforms of APP (APP common, 770 and 695), in the cortex and hippocampus of the treated and the control groups were measured. Significant increase in APP 770 expression level while a substantial decrease was observed for SOD1, Prdx6 and APP 695 expression in Pb-treated groups. Interestingly, the deranged expression levels were significantly normalized by the treatment with ethanol extracts of Foeniculum vulgare seeds (specifically at dose of 200 mg/kg/day). Furthermore, the Pb-induced morphological deterioration of cortical neurons was significantly improved by the ethanol extracts of Foeniculum vulgare seeds. In conclusion, the present findings highlight the promising therapeutic potential of Foeniculum vulgare to minimize neuronal toxicity by normalizing the expression levels of APP isoforms and oxidative stress markers.
50% Ethanol extract of Orthosiphon stamineus modulates genotoxicity and clastogenicity induced by mitomycin C

Al-Dualimi DW, Shah Abdul Majid A, Al-Shimary SFF, Al-Saadi AA, Al Zarzour R, Asif M, et al.

Drug Chem Toxicol, 2018 Jan;41(1):82-88.
PMID: 28635332 DOI: 10.1080/01480545.2017.1317785

Herbal products contain a variety of compounds which may be useful in protecting against cellular damage caused by mutagens. Orthosiphon stamineus (O.s) also known as Cat whiskers. The herb has been shown anti-oxidative properties and can modulate key cellular proteins that have cytoprotective effect. The study aimed to evaluate the effects of different doses (250, 500 and 1000 mg kg-1) of 50% ethanol extract of O.s (Et. O.s) on micro-nucleated polychromatic erythrocytes (MNPCE), Polychromatic to normachromatic erythrocytes ratio (PCE/NCE), Mitotic index (MI), and Chromosomal aberration (CA) in Bab/c mice. Moreover, these parameters were used to evaluate the anti-genotoxic and clastogenic potencies of (Et. O.s) against mitomycin c (MMC) that interact with biological molecules and induce genotoxic and clastogenic disorders in non-tumor cells. MMC (4 mg kg-1) was injected intraperitoneally (i.p.) to the mice before and after treatment with three different doses of (Et. O.s). The results indicated that the extract at different doses did not show significant (p ≥ 0.05) differences in (MNPCE), (PCE/NCE) ratios, and (CA) values. The higher doses sowed high (MI) values compared with untreated control group. MMC showed significant increase (p ≤ 0.001) in (MNPCE), (CA) and reduce (PCE/NCE) and (MI) values compared with untreated control group. Treatment with (Et. O.s) at different doses before and after MMC injection showed to modulate MNPCE, PCE/NCE ratios, CA and MI values in mice bone marrow cells suggesting genoprotective potential of this plant extract.
Anticlastogenic, antimutagenic, and cytoprotective properties of Orthosiphon stamineus ethanolic leaves extract

Al-Dulaimi DW, Shah Abdul Majid A, M Baharetha H, Ahamed MBK, Faisal SF, Al Zarzour RH, et al.

Drug Chem Toxicol, 2020 Apr 22.
PMID: 32321321 DOI: 10.1080/01480545.2020.1749652

Orthosiphon stamineus (O.S) is widely consumed for its medidcinal value including anti-inflammatory, anti-infective, and diuretic properties. The present study evaluates the cytoprotective, anti-mutagenic, and anticlastogenic efficacies of standardized extract of Orthosiphon stamineus. Normal liver cell line (WRL68) exposed to hydrogen peroxide and serum-deprived media as insults to evaluate cytoprotective and glutathione activation activities of (Et. O. s). Salmonella typhimurium TA98 and TA100 exposed to different concentrations of (Et. O. s). The influence of Et. O. s on mitotic, replicative indices as well as chromosomal aberration (CA) and sister chromatid exchange (SCE) induced in human peripheral blood lymphocytes by mitomycin C (MMC). The Et. O.s proved to be a potent scavenger for hydrogen peroxide and other free radicals in serum-depraved media, which showed to stimulate glutathione production in liver cells line. Moreover, it did not induce mutations in S. typhimurium subspecies TA98 and TA100. The standardized extract exhibited powerful antimutagenic activities as verified against both 2-nitrofluorene and sodium azide in S. typhimurium TA98 and TA100 cells, respectively. Cytogenetic tests showed high concentrations of Et. O. s to reduce the values of mitotic and replicative indices without any accompanying side effects, such as chromosomal abnormalities or SCE. To ameliorate MMC effects, pretreatment with the extract proofed to be efficient protocol. These data suggests that O. stamineus extract could be useful as cytoprotective, antimutagenic, and anticlastogenic efficacies, which owes to its potent chemoprevention, antioxidant, and glutathione activation properties.
The sub-acute toxicity of kavalactone in rats: a study of the effect of oral doses and the mechanism of toxicity in combination with ethanol

Abdulabbas Hasan M, Mohan S, Rahman HS, Othman HH, Hamasalih Omer S, Farasani A

Drug Chem Toxicol, 2023 May;46(3):588-596.
PMID: 35506235 DOI: 10.1080/01480545.2022.2069803

Kava is a herbal supplement and beverage made from the Piper methysticum plant, which is known for its recreational use as a mood enhancer, relaxation, as well as pain relief for centuries. Kava is widely used among alcoholics, but it is dangerous and potentially fatal. The objectives of this study were to examine the sub-acute toxicity effects of different doses of 70% kavalactone (KL) in rats by oral application, as well as to elucidate the mechanisms of toxicity alone and in combination with ethanol (EtOH). The most common side effects observed were abnormal breathing, ataxia, lethargy, loss of appetite, indigestion, and loss of coordination, especially in the 800 mg/kg bw, po bodyweight dosage of kava treatment group alone, and in combination with EtOH. In the sub-acute study, there were dose-related decreases in body weight, feed intake, and water consumption rates. Gross and histopathological findings revealed that the liver was abnormal in color, size, consistency, and the weight significantly increased at a dose of 800 mg/kg bw, po, with KL alone and a greater increase in combination with EtOH. Hepatocellular hypertrophy (HP) and necrosis with Kupffer cells hyperplasia were observed in the periacinar zone of all rats dosed with KL (800 mg/kg bw, po) alone, and extensive changes were observed in combination with EtOH. The periportal (Z1) and mid-zonal (Z2) areas of hepatocytes were less affected as compared to the periacinar zone. These results demonstrate that EtOH exacerbated the sedative and hypnotic activity of KL, and markedly increased toxicity. The histopathological results supported the clinical and biochemical findings and the severity of hepatic damage in a dose-dependent manner.
Study on the acute toxicity of sodium taurocholate via zebrafish mortality, behavioral response, and NMR-metabolomics analysis

Abdulazeez I, Ismail IS, Mohd Faudzi SM, Christianus A, Chong SG

Drug Chem Toxicol, 2024 Jan;47(1):115-130.
PMID: 37548163 DOI: 10.1080/01480545.2023.2242005

Sodium taurocholate (NaT) is a hydrophobic bile salt that exhibits varying toxicity and antimicrobial activity. The accumulation of BSs during their entero-hepatic cycle causes cytotoxicity in the liver and intestine and could also alter the intestinal microbiome leading to various diseases. In this research, the acute toxicity of sodium taurocholate in different concentrations (3000 mg/L, 1500 mg/L, 750 mg/L, 375 mg/L, and 0 mg/L) was investigated on four months old zebrafish by immersion in water for 96 h. The results were determined based on the fish mortality, behavioral response, and NMR metabolomics analysis which revealed LC50 of 1760.32 mg/L and 1050.42 mg/L after 72 and 96 h treatment, respectively. However, the non-lethal NaT concentrations of 750 mg/L and 375 mg/L at 96 h exposure significantly (p ≤ 0.05) decreased the total distance traveled and the activity duration, also caused surface respiration on the zebrafish. Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) revealed that the metabolome of the fish treated with 750 mg/L was discriminated from that of the control by PC1. Major significantly downregulated metabolites by NaT-induction include valine, isoleucine, 2-hydroxyvalerate, glycine, glycerol, choline, glucose, pyruvate, anserine, threonine, carnitine and homoserine. On the contrary, taurine, creatine, lactate, acetate and 3-hydroxybutyrate were upregulated suggesting cellular consumption of lipids, glucose and amino acids for adenosine triphosphate (ATP) generation during immune and inflammatory response. whereby these metabolites were released in the process. In conclusion, the research revealed the toxic effect of NaT and its potential to trigger changes in zebrafish metabolism.
1H NMR-metabolomics studies on acute toxicity effect of lead in adult zebrafish (Danio rerio) model

Chong SG, Ismail IS, Chong CM, Mad Nasir N, Saleh Hodin NA

Drug Chem Toxicol, 2024 Sep;47(5):573-586.
PMID: 38726945 DOI: 10.1080/01480545.2024.2346751

Zebrafish (Danio rerio) is ideal for studying the effects of toxins like lead or plumbum (Pb) which persist in the environment and harm body systems when absorbed. Increasing Pb concentration could result in a higher mortality rate and alteration of behavior and metabolism. The present study evaluates the acute toxicity effect of Pb on metabolome and behavior in adult zebrafish. The zebrafish were exposed to various Pb concentrations ranging from 0 to 30 mg/L for different periods (24, 48, and 72 h) before the fish samples were subjected to Nuclear Magnetic Resonance (NMR)-multivariate data analysis (MVDA) with additional support from behavioral assessment. The behavior of zebrafish was significantly altered after Pb inducement and the differential metabolites increased in low (5 mg/L) while decreased in high (10 mg/L) Pb concentrations. An ideal Pb induction could be achieved by 5 mg/L concentration in 24 h, which induced significant metabolite changes without irreversible damage. Continuing research on the effects of lead toxicity is crucial to develop effective prevention and treatment strategies.

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