Effects of benzothiazole on the xenobiotic metabolizing enzymes and metabolism of acetaminophen

Benzothiazole (BT) is present in tobacco smoke and widely used for industrial and pharmaceutical purposes. In this study we have investigated the influence of BT on the activities of hepatic cytochrome P450 monooxygenases (P450s) and UDP-glucuronyltransferase (UDP-GT), sulphotransferase and glutathione-S-transferase (GST) in male Sprague-Dawley rats. We also examined if BT would change the metabolism and toxification of acetaminophen (AA) through modulation of metabolizing enzymes. Benzothiazole (1 mmol kg(-1), p.o., 5 days) markedly increased the enzyme activities of P4501A1, 1A2, 2B1, 3A4, 2E1, UDP-GT and GST in liver. Pretreatment with BT significantly decreased the amount of total AA recovered in bile to 68.5% of controls, mainly as a consequence of reduced AA-glucuronide conjugate (35.3% of controls), whereas the AA-glutathione conjugate (AA-GS) was augmented to 1.6-fold. After pretreatment with BT, potentiation of the hepatotoxicity by AA (400 mg kg(-1), i.p., 24 h) was observed by measuring serum alanine aminotransferase activities in ICR mice. These results indicate that: BT is a potent inducer of P450s and phase II metabolizing enzymes; and the increase of AA-GS conjugate and aggravation of AA hepatotoxicity by BT may be related to induction of P450s.     

Modification of the pharmacokinetics of ortophen and its analgesic activity by inducers and inhibitors of xenobiotic metabolism enzymes and thiamine diphosphate

Phenobarbital administered in a dose of 70 mg/kg intraperitoneally (once a day for 4 days) was shown to accelerate ortophen elimination from blood of rats and to decrease its analgesic activity. Administration of cimetidine (100 mg/kg, intragastrically once a day for 5 days), cobalt chloride (10 mg/kg, subcutaneously twice) and thiamine diphosphate (10 mg/kg, intraperitoneally once a day for a week) was found to slow down elimination of ortophen from blood and to enhance its analgesic effect. Cimetidine slows down ortophen elimination from blood of the patients.     

A catalogue of polymorphisms related to xenobiotic metabolism and cancer susceptibility

High-throughput genotyping technology of multiple genes based on large samples of cases and controls are likely to be important in identifying common genes which have a moderate effect on the development of specific diseases. We present here a comprehensive list of 313 known experimentally confirmed polymorphisms in 54 genes which are particularly relevant for metabolism of drugs, alcohol, tobacco, and other potential carcinogens. We have compiled a catalog with a standardized format that summarizes the genetic and biochemical properties of the selected polymorphisms. We have also confirmed or redesigned experimental conditions for simplex or multiplex PCR amplification of a subset of 168 SNPs of particular interest, which will provide the basis for the design of assays compatible with high-throughput genotyping.     

Tannins, xenobiotic metabolism and cancer chemoprevention in experimental animals.

Tannins are plant polyphenolic compounds that are contained in large quantities in food and beverages (tea, red wine, nuts, etc.) consumed by humans daily. It has been shown that various tannins exert broad cancer chemoprotective activity in a number of animal models. This review summarizes the recent literature regarding both the mechanisms involved, and the specific organ cancer models used in laboratory animals. An increasing body of evidence demonstrates that tannins act as both anti-initiating and antipromoting agents. In view of the fact that tannins may be of valid medicinal efficacy in human clinical trials, the present review attempts to integrate results from animal studies, and considers their possible application in humans.     

N,N-Dimethylformamide-induced effects on hepatic and renal xenobiotic enzymes with emphasis on aldehyde metabolism in the rat

Male Wistar rats were dosed with N,N-dimethylformamide (DMF) in drinking water at four concentration levels (0,0.1,0.5 or 1.0 g/l) for 2 or 7 weeks. Upon evaluation of the effects in the liver increased values were found for the following parameters: liver/body weight-ratio, GSH content, ethoxycoumarin O-deethylase and UDPglucuronosyltransferase activities. The GSH content, deethylase activity and, transiently, the glucuronidation activity were slightly increased also in the kidneys. Oxidative N-demethylation of DMF by hepatic microsomes in vitro was not enhanced by oral treatment. No DMF-dependent formaldehyde liberation in vitro could be detected under conditions where formaldehyde liberation from N,N-dimethylnitrosamine could be demonstrated. However, the endogenous rate of formaldehyde generation by liver microsomes isolated from DMF-treated rats was enhanced with the highest oral dose of DMF. The daily intake of DMF lowered the activities of both formaldehyde and propionaldehyde dehydrogenases in the liver soluble fraction. No inhibition of these dehydrogenases was shown in vitro by DMF (less than or equal to 10 mM) or by its main urinary metabolite N-methylformamide (less than or equal to 10 mM). The observed impairment of aldehyde oxidation in liver and kidneys of the rat after the DMF intake could explain the mechanism behind the alcohol intolerance observed in man after DMF-exposure.     

Occupational bladder cancer: Polymorphisms of xenobiotic metabolizing enzymes,exposures, and prognosis

ABSTRACT

Approximately 7% of all bladder cancer cases in males are associated with occupation. The question arises whether the use of genome-wide association studies was able to identify bladder cancer risk factors that may modulate occupational bladder cancer risk and prognosis. One hundred and forty-three bladder cancer cases with suspected occupational bladder cancer and 337 controls were genotyped for the following polymorphisms: N-acetyltransferase 2 (NAT2), glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), UDP-glucuronyltransferase 1A rs11892031 (UGT1A), rs9642880 (close to c-MYC), and rs710521 (close to TP63). The most relevant polymorphisms for occupational bladder cancer risk were GSTM1 and UGT1A, especially when co-occurring (GSTM1 negative and rs11892031[A/A]: 48% cases vs. 38% controls, OR 1.47, 95% CI 0.99–2.20). The effect was more pronounced in smokers. GSTM1 negative genotype occurred more frequently in cancer cases exposed to aromatic amines, carbolineum, and in painters and varnishers. UGT1A (rs11892031[A/A]) was found frequently in cases exposed to carbolineum, crack test spray, PAH, and in painters and varnishers. All investigated polymorphisms except rs710521 (TP63) seemed to exert an impact on recurrence risk. Relapse-free times were shorter for NAT2 slow and ultra-slow, GSTT1 positive and GSTM1 negative cases. Occupational bladder cancer cases with a number of risk variants displayed significantly shorter relapse-free times compared to cases with few, less relevant risk alleles as evidenced by median difference 8 months. In conclusion, in the present, suspected occupational bladder cancer cases phase II polymorphisms involved in bladder carcinogen metabolism modulate bladder cancer recurrence. Most relevant for bladder cancer risk were GSTM1 and UGT1A but not NAT2.     

Statistical methods for detecting genetic interactions: a head and neck squamous-cell cancer study

Tobacco smoke and occupational exposures to chemicals such as polycyclic aromatic hydrocarbons (PAHs) are, aside from alcohol, the major risk factors for development of head and neck squamous-cell cancer (HNSCC). In this study, new statistical methods were applied. We employ new statistical methods to detect genetic interactions perhaps of higher order, that might play a role in developing HNSCC. The underlying study comprises 312 HNSCC cases and 300 controls. Single-nucleotide polymorphisms (SNPs) of PAH metabolizing and repair enzymes, somatic p53 mutations, and tobacco smoke were examined. Key statistical tools for our analysis are methods of unsupervised and supervised learning. In unsupervised learning, one performs cluster analyses based on well-known and new distance measures to find differences in the SNP patterns of cases and controls, and to understand the role of p53. Our main goal in supervised learning was to identify SNPs and SNP interactions that are likely to alter the susceptibility to HNSCC. Logic regression, a classification method well suited for SNPs, was employed as well as a Bayesian generalization that allows for incorporating additional expert knowledge. These methods detected several important interactions, such as an association between CYP1B1, tobacco smokes and p53 mutations and some interactions between CYP1B1 and glutathione S-transferases in smokers, which included a three-way interaction between CYP1B1, CYP2E1-70G>T, and GSTP1 (exon 5).     

Pharmacotherapy for squamous-cell carcinoma of the head and neck

Introduction: Squamous-cell carcinoma of the head and neck (HNSCC) is one of the most common malignancies, the treatment of which constitutes a therapeutic challenge.

Areas covered: The purpose of this review is to provide an update on the pharmacotherapy for the treatment of HNSCC focusing mainly on molecular-targeted therapies. An overview of the different novel therapeutic agents that can selectively inhibit signaling pathways and receptors that are involved in the development and progression of cancer especially in HNSCC is presented.

Expert opinion: The treatment of HNSCC is traditionally based on surgery and radiotherapy for early-stage HNSCC; however, chemotherapy is no longer used only for palliation, and individualized patient treatment assisted by molecular-targeted therapies represents a future therapeutic challenge.     

Nasal cavity enzymes involved in xenobiotic metabolism: effects on the toxicity of inhalants.

A decade ago, the ability of nasal tissues to metabolize inhalants was only dimly suspected. Since then, the metabolic capacities of nasal cavity tissues has been extensively investigated in mammals, including man. Aldehyde dehydrogenases, cytochrome P-450-dependent monooxygenases, rhodanese, glutathione transferases, epoxide hydrolases, flavin-containing monooxygenases, and carboxyl esterases have all been reported to occur in substantial amounts in the nasal cavity. The contributions of these enzyme activities to the induction of toxic effects from inhalants such as benzo-a-pyrene, acetaminophen, formaldehyde, cocaine, dimethylnitrosamine, ferrocene, and 3-trifluoromethylpyridine have been the subject of dozens of reports. In addition, the influence of these enzyme activities on olfaction and their contribution to vapor uptake is beginning to receive attention from the research community. Research in the next decade promises to provide answers to the many still unanswered questions posed by the presence of the substantial xenobiotic metabolizing capacity of the nasal cavity.     

Pharmacotherapy for squamous-cell carcinoma of the head and neck

INTRODUCTION: squamous-cell carcinoma of the head and neck (HNSCC) is one of the most common malignancies, the treatment of which constitutes a therapeutic challenge. AREAS COVERED: the purpose of this review is to provide an update on the pharmacotherapy for the treatment of HNSCC focusing mainly on molecular-targeted therapies. An overview of the different novel therapeutic agents that can selectively inhibit signaling pathways and receptors that are involved in the development and progression of cancer especially in HNSCC is presented. EXPERT OPINION: the treatment of HNSCC is traditionally based on surgery and radiotherapy for early-stage HNSCC; however, chemotherapy is no longer used only for palliation, and individualized patient treatment assisted by molecular-targeted therapies represents a future therapeutic challenge.     

乳腺癌相关糖复合物糖链研究进展

乳腺癌是妇科疾病中发病率最高的恶性肿瘤,从糖复合物糖链变化的角度来探讨乳腺癌的发病机制是当前疾病糖组学研究的热点。该文综述近年来乳腺细胞癌变过程中细胞膜及细胞外基质中糖蛋白、糖脂、蛋白聚糖等糖复合物的糖链变化情况,并对研究中存在的问题进行了探讨。     

Occupational exposure to low levels of benzene: Biomarkers of exposure and nucleic acid oxidation and their modulation by polymorphic xenobiotic metabolizing enzymes

This study investigated nucleic acid oxidation associated with exposure to benzene at low levels in 239 workers recruited among traffic policemen, taxi drivers and gasoline pump attendants of the city of Parma (Italy). Biomarkers of exposure, namely urinary t,t-muconic acid (t,t-MA) and S-phenylmercapturic acid (S-PMA), urinary cotinine, and urinary biomarkers of nucleic acid oxidation, namely 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo), 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydroguanine (8-oxoGua) were determined by liquid chromatography–tandem mass spectrometry. Relevant polymorphisms of NAD(P)H:quinone oxidoreductase (NQO1), glutathione S-transferases M1-1 (GSTM1), T1-1 (GSTT1), and A1 (GSTA1) were characterized by polymerase chain reaction-based methods in a subgroup of subjects. Biomarkers of nucleic acid oxidation were correlated with each other (r ≥ 0.32, p < 0.0001) and with exposure biomarkers (r ≥ 0.28, p < 0.0001). Multiple linear regression models including age, sex and smoking habits as independent variables demonstrated that benzene exposure is associated with oxidation damage to nucleic acid, particularly to RNA (p < 0.0001) and is modulated by the NQO1 polymorphism. The study confirmed a significant modulating effect of GSTM1 (p = 0.010), GSTT1 (p = 0.023) and GSTA1 (p = 0.048) polymorphisms on S-PMA excretion, with a significant interaction between GSTM1 and both GSTT1 and GSTA1 (p = 0.006 and p = 0.037, respectively).     

Colon cancer chemopreventive efficacy of silibinin through perturbation of xenobiotic metabolizing enzymes in experimental rats

Our findings reported so far demonstrate that silibinin modulates gut microbial enzymes, colonic oxidative stress and Wnt/β-catenin signaling, to exert its antiproliferative effect against 1,2 di-methylhydrazine (DMH) induced colon carcinogenesis. Since xenobiotic metabolizing enzymes play a crucial role in carcinogen activation and metabolism, we aimed to explore the effect of silibinin on xenobiotic metabolizing enzymes during DMH induced colon carcinogenesis. Male albino rats were randomly divided into six groups. Group 1 served as control and group 2 rats received 50mg/kg body weight of silibinin p.o. every day. Groups 3-6 rats were given DMH at a dose of (20mg/kg body weight subcutaneously) once a week for 15 weeks to induce colonic tumors. In addition to DMH, group 4 (initiation), group 5 (post-initiation) and group 6 (entire period) rats received silibinin (50mg/kg body weight, p.o., everyday) at different time points during the experimental period of 32 weeks. Rats exposed to DMH alone showed increased activities of phase I enzymes (cytochrome b5, cytochrome b5 reductase, cytochromeP450, cytochromeP450 reductase, cytochromP4502E1) and decreased activities of phase II enzymes (Uridine diphospho glucuronyl transferase, Glutathione-S-transferase and DT-Diaphorase) in the liver and colonic mucosa as compared to control rats. Silibinin supplementation modulates the xenobiotic metabolizing enzymes favoring carcinogen detoxification. Evaluation of lipid peroxidation and antioxidants status showed that silibinin supplementation counteracts DMH induced hepatic and circulatory oxidative stress. Tumor burden in experimental animals was assessed both macroscopically and microscopically in the colon tissues. Our findings emphasize the potential chemopreventive action of silibinin against DMH induced colon carcinogenesis.     

Polymorphisms of xenobiotic metabolizing enzymes in bladder cancer patients of the Semmelweis University Budapest,Hungary

ABSTRACT

Polymorphic xenobiotic metabolizing enzymes such as N-acetyltransferase 2 (NAT2) or glutathione S-transferase M1 (GSTM1) are known to modulate bladder cancer risk. As no apparent data were available from Hungary, a former member of the eastern European economic organization, a study was performed in Budapest. In total, 182 bladder cancer cases and 78 cancer-free controls were investigated by questionnaire. Genotypes of NAT2, GSTM1, GSTT1, rs1058396 and rs17674580 were determined by standard methods. Current smokers’ crude odds ratio (OR) (3.43) and former smokers crude OR (2.36) displayed a significantly increased bladder cancer risk. The risk rose by a factor of 1.56 per 10 pack years. Exposure to fumes was associated with an elevated bladder cancer risk (23% cases, 13% controls). Sixty-four % of the cases and 59% of controls were slow NAT2 acetylators. It was not possible to establish a particular impact of NAT2*6A and *7B genotypes (15 cases, 8%, 5 controls, 7%). GSTT1 exerted no marked influence on bladder cancer (negative 21% cases vs. 22% controls). The portion of GSTM1 negative bladder cancer patients was increased (63% cases vs. 54% controls). The SLC14A1 SNPs rs1058396[AG/GG] and the nearby rs17674580[CT/TT] occurred more frequently in cases (79% and 68%) than controls (77% and 55%). The portion of GSTM1 negative bladder cancer patients is comparable with portions reported from other industrialized areas like Lutherstadt Wittenberg/Germany (58%), Dortmund/Germany (70%), Brescia/Italy (66%) or an occupational case-control series in Germany (56%). Data indicate that GSTM1 is a susceptibility factor for environmentally triggered bladder cancer rather than for smoking-mediated bladder cancer.     

Molecular and structural aspects of xenobiotic carbonyl metabolizing enzymes. Role of reductases and dehydrogenases in xenobiotic phase I reactions

The major metabolic pathways involved in synthesis and disposition of carbonyl and hydroxyl group containing compounds are presented, and structural and functional characteristics of the enzyme families involved are discussed. Alcohol and aldehyde dehydrogenases (ADH, ALDH) participate in oxidative pathways, whereas reductive routes are accomplished by members of the aldo-keto reductase (AKR), short-chain dehydrogenases/reductases (SDR) and quinone reductase (QR) superfamilies. A wealth of biochemical, genetic and structural data now establishes these families to constitute important phase I enzymes.