Optical substrates for drug-metabolizing enzymes: Recent advances and future perspectives

Drug-metabolizing enzymes (DMEs), a diverse group of enzymes responsible for the metabolic elimination of drugs and other xenobiotics, have been recognized as the critical determinants to drug safety and efficacy. Deciphering and understanding the key roles of individual DMEs in drug metabolism and toxicity, as well as characterizing the interactions of central DMEs with xenobiotics require reliable, practical and highly specific tools for sensing the activities of these enzymes in biological systems. In the last few decades, the scientists have developed a variety of optical substrates for sensing human DMEs, parts of them have been successfully used for studying target enzyme(s) in tissue preparations and living systems. Herein, molecular design principals and recent advances in the development and applications of optical substrates for human DMEs have been reviewed systematically. Furthermore, the challenges and future perspectives in this field are also highlighted. The presented information offers a group of practical approaches and imaging tools for sensing DMEs activities in complex biological systems, which strongly facilitates high-throughput screening the modulators of target DMEs and studies on drug/herb‒drug interactions, as well as promotes the fundamental researches for exploring the relevance of DMEs to human diseases and drug treatment outcomes.

Relationship between homocysteine metabolizing enzyme gene polymorphism and prognosis of multiple myeloma in Han nationality / 中国医师进修杂志

Objective:To investigate the clinical relationship between homocysteine (Hcy) metabolizing enzyme gene polymorphism and poor prognosis of multiple myeloma (MM) in Han nationality.Methods:One hundred and twenty-eight MM patients of Han nationality admitted to the First Affiliated Hospital of Hebei North University from February 2018 to March 2020 were selected as the disease group, and 120 healthy volunteers of Han nationality were recruited as the control group at the same time. Blood samples were taken to detect plasma Hcy level and Hcy metabolizing enzyme gene polymorphism, including methylenetetrahydrofolate reductase(MTHFR) C677T, MTHFRA1298C, methionine synthase reductase(MTRR) A66G, cystathionine beta-synthase(CBS) 844ins68 and methionine synthase (MS) A2756G. The patients in the disease group were treated with conventional methods , followed up for 1 year after treatment, and the incidence of poor prognosis was counted. Plasma Hcy level, genotype distribution and allele frequency of Hcy metabolic enzymes were compared between the two groups. Logistic multiple regression analysis was used to analyze the association of Hcy metabolizing enzyme gene polymorphism with MM poor prognosis in Han nationality.Results:The plasma Hcy level in the disease group was higher than that in the control group: (15.01 ± 2.98) μmol/L vs. (8.45 ± 1.69) μmol/L, there was statistical difference ( P<0.05). The frequency of TT genotype and T allele of MTHFRC677T locus in the disease group were higher than those in the control group : 26.56% vs. 6.67% , 29.30 vs. 16.25%; while the frequency of CT genotype in the disease group was lower than that in the control group: 5.47% vs. 19.17% , there were statistical differences ( P<0.05). There were no significant differences in genotype distribution and allele frequency of other gene loci between the two groups ( P>0.05). The incidence of poor prognosis in the disease group was 49.22%(63/128). Age, platelet count, serum β 2 microglobulin level, serum κ light chain level, plasma Hcy level and TT genotype of MTHFRC677T locus were the influencing factors of poor prognosis in the disease group ( OR = 7.286, 0.545, 6.841, 6.284, 8.117 and 8.440; P<0.05). Conclusions:The plasma Hcy level, TT genotype and T allele frequency of MTHFRC677T locus in MM patients of Han nationality are higher than those in healthy people, while the CT genotype frequency is lower than that in healthy people. The poor prognosis of MM in Han nationality is related to plasma Hcy level and TT genotype of MTHFRC 677T locus.

Current trends in drug metabolism and pharmacokinetics

Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion (ADME) processes of a drug. Understanding PK properties is essential for drug development and precision medication. In this review we provided an overview of recent research on PK with focus on the following aspects: (1) an update on drug-metabolizing enzymes and transporters in the determination of PK, as well as advances in xenobiotic receptors and noncoding RNAs (ncRNAs) in the modulation of PK, providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy; (2) current status and trends in assessing drug-drug interactions, especially interactions between drugs and herbs, between drugs and therapeutic biologics, and microbiota-mediated interactions; (3) advances in understanding the effects of diseases on PK, particularly changes in metabolizing enzymes and transporters with disease progression; (4) trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies; (5) emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes, especially non-P450s. Existing challenges and perspectives on future directions are discussed, and may stimulate the development of new research models, technologies, and strategies towards the development of better drugs and improved clinical practice.

Comparison of methods for stable co-expression of different subtype drug-matabolizing enzymes in HepG2 cells by piggyBac transposon / 中国药理学与毒理学杂志

OBJECTIVE To study the methodology of achieving stable co-expression of drug-metab?olizing enzymes in the HepG2 cells by the piggyBac (PB) transposon system. METHODS N-terminal attachment of enhanced green fluorscent protein plasmid (pEGFP- N2) and 2A peptide linked recombinant PB transposon plasmid containing dual-genes encoding drug metabolizing enzymes cyto?chrome P450 3A4 (CYP3A4) and CYP2C19 (pPB-CYP3A4-2A-2C19) were transfected into HepG2 cells respectively by Lipofectamine?LTX reagent, GenJetTM (Ver.Ⅱ) reagent and Neon?Transfection System reagent, which were widely used for large-sized DNA fragments transfection. 48 h later, the transfection efficiency and cell toxicity were detected and compared between the three methods so as to find a method with relatively high efficiency and low toxicity for later transfection.Then,three groups of recombinant PB transposons-single-gene transposon (PB-CYP3A4), 2A peptide linked dual-gene transposon (PB-CYP3A4-2A-2C19) and multiple single-gene transposon mixture〔PB-CYP3A4, PB-CYP2C8, PB-CYP2A6, organic anion transporting polypeptide 1B1 PB transposon (PB-OATP1B1)〕-were transfected into HepG2 cells respectively with the above established method.The puromycin (Puro)-resistant and GFP positive cell clones were picked up and further cultured. The mRNA, protein and metabolic levels of drug-metabolizing enzymes in monoclonal cell lines were detected by quantitative real-time PCR,Western blotting and high performance liquid chromatography-tandem mass spectrometry respectively after screening by Puro and green fluorescence. Comparisons of different groups were made using statistical analysis. RESULTS The comparison of three different transfection methods indi?cated that the transfection efficiency of GenJetTMwas up to(94.2±2.5)% and (89.3±3.3)%,significantly higher than those of the other two methods (P<0.01), along with lower cytotoxicity. Then GenJetTMwas chosen for later transfection. In the Puro-resistant monoclonal cell lines of single transposon PB-CYP3A4,PB-CYP3A4-2A-2C19 groups,the mRNA,protein and enzyme activity levels of drug-metabo?lizing enzymes were significantly increased respectively.The recombinant transposon (PB-CYP3A4-2A-2C19) containing 2A peptide could achieve stable and efficient co-expression of two metabolizing enzymes CYP3A4 and CYP2C19,while the expression of drug-metabolizing enzymes remained unbal?anced and random in those of multiple single-gene transposon mixture group (PB-CYP3A4, PB-CYP2C8,PB-CYP2A6,PB-OATP 1B1)(CYP3A4 was expressed in some cell clones only).CONCLUSION GenJetTM could be an effective method for the PB recombinant transposon transfection into HepG2 cells, by which the PB transposon could mediate stable expression of drug-metabolizing enzymes. In terms of multi-gene expression,a low and unbalanced expression is found by multiple transposons co-transfection method,which is different from that by virus mediated method.In contrast,mono-PB trans?poson linked by 2A peptide can achieve stable expression of multi-genes.

Advances in Metabolizing Enzymes and Transporters Mediated Capsaicin-Drug Interaction / 中国药学杂志

With the continuously clinical study of capsaicin, capsaicin-drug interaction has become increasingly prominent. In recent years, the studies indicate that capsaicin shows a significant inducing or inhibitory effect on a variety of drug metabolism enzymes and transporters, thereby leading to the occurrence of complex drug interactions and affecting the other drugs in vivo process. In this paper, the modulation effect of capsaicin on drug metabolizing enzymes and transporters by reviewing the relevant research at home and abroad in recent years were summarized, and the drug-drug interactions associated with capsaicin in order to provide theoretical guidance for clinical rational drug use were explored. Furthermore, complex drug-drug interaction studies can be provided with prior examples.

The impacts of Elaeagnus umbellata Thunb. leaf and fruit aqueous extracts on mice hepatic, extrahepatic antioxidant and drug metabolizing enzymes related structures

ABSTRACT In this work, the potential chemopreventive activities of Elaeagnus umbellata fruit aqueous (EUFA) and leaf aqueous (EULA) extracts focusing on the modulatory influence of xenobiotic metabolizing enzymes (XMEs), antioxidant enzymes, glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), lactate dehydrogenase (LDH) activity, lipid peroxidation (LP), sulfhydryl groups were investigated in the hepatic and extrahepatic organs of Swiss albino mice (50 and 100 mg/kg body wt given orally for 14 days) and compared with BHA (0.75 % in diet). The modulatory and chemopreventive properties of two different doses EUFA and EULA were observed for cytochrome P450, cytochrome b5, sulfhydryl groups, NADPH-cytochrome P450 reductase, NADH-cytochrome b5 reductase, 7-ethoxyresorufin-deethylase and N,N-dimethylaniline N-oxidase activities in the liver and compared with BHA as a standard. The activities of glutathione S-transferase (GST) and DT-diaphorase (DTD) showed a significant increase in the kidney, forestomach, heart and brain at both doses of EUFA and EULA. The results of EULA-treated groups were found a notable increase in LDH, G6PD, 6PGD, GST and DTD activities. Superoxide dismutase level in liver, kidney and heart exhibited a significant increase at both doses of EULA. Glutathione reductase activity was a remarkable level at high dose of EUFA in liver, kidney and EULA in kidney. Both doses of EUFA were effective in inducing glutathione peroxidase activitiy in heart. The levels of LP at low and high doses of EULA-treated and EUFA-treated were effective in liver and kidney, respectively. The present results demonstrate that significant effects in the level of XMEs and antioxidant enzymes of EUFA and EULA are remarkable for modulating roles and natural chemoprevention properties and therefore is considered for a valuable natural source.

Role of drug transporters and metabolizing enzymes in pharmacokinetics of antibiotics / 药物评价研究

In recent years,the research on drag transporters has made great progress,more and more transporters have been found and studied,and they have shown important roles in the transport of drug across the cellular membrane.Various transporters,including uptake transporters and effiux transporters,have important effects on the pharmacokinetics and drug-drug interactions.Studies have shown that the process in vivo of most of the antibiotics was related to transporters and metabolizing enzymes (cytochrome P450 and CYP450).Therefore,this article summarized the latest research progress in pharmacokinetics and drug-drug interactions of transporters and CYP450,so that provides evidence for clinical rational use of antibiotics.

Genetic polymorphisms in NAT1, NAT2, GSTM1, GSTP1 and GSTT1 and susceptibility to colorectal cancer among Filipinos

@#Objectives. Polymorphisms in metabolic genes which alter rates of bioactivation and detoxification have been shown to modulate susceptibility to colorectal cancer. This study sought to evaluate the colorectal cancer risk from environmental factors and to do polymorphism studies on genes that code for Phase I and II xenobiotic metabolic enzymes among Filipino colorectal cancer patients and matched controls. Methods. A total of 224 colorectal cancer cases and 276 controls from the Filipino population were genotyped for selected polymorphisms in GSTM1, GSTP1, GSTT1, NAT1 and NAT2. Medical and diet histories, occupational exposure and demographic data were also collected for all subject participants.Results. Univariate logistic regression of non-genetic factors identified exposure to UV (sunlight) (OR 1.99, 95% CI: 1.16-3.39) and wood dust (OR 2.66, 95% CI: 1.21-5.83) and moldy food exposure (OR 1.61, 95% CI:1.11-2.35) as risk factors; while the NAT2*6B allele (recessive model OR 1.51, 95% CI :1.06-2.16; dominant model OR 1.87, 95% CI: 1.05-3.33) and homozygous genotype (OR 2.19, 95% CI: 1.19-4.03) were found to be significant among the genetic factors. After multivariate logistic regression of both environmental and genetic factors, only UV radiation exposure (OR 2.08, 95% CI: 1.21-3.58) and wood dust exposure (OR 2.08, 95% CI: 0.95-5.30) remained to be significantly associated with increasing colorectal cancer risk in the study population.Conclusion. This study demonstrated that UV sunlight and wood dust exposure play a greater role in influencing colorectal cancer susceptibility than genotype status from genetic polymorphisms of the GST and the NAT` genes.

Advances in the Modulation of Quercetin on Drug Metabolizing Enzymes / 中国药师

Objective: To summarize the recent research progress in the influence of quercetin on drug metabolizing enzymes. Methods:By referring to the relevant literatures at home and abroad in recent years, the paper summarized, analyzed and concluded the the influence of quercetin on drug metabolizing enzymes. Results: Quercetin could modulate the phase Ⅰmetabolic enzyme cyto-chrome P450 ( CYP) and the phase Ⅱ metabolic enzymes uridine diphosphate - glucuronosyltransferase enzyme ( UGTs) , sulfotrans-ferase ( SULTs) and glutathione S-transferase ( GSTs) to influence the in vitro and in vivo metabolism of a lot of drugs. Meanwhile, the modulation of quercetin on the metabolic enzymes demanded the participation of various nuclear receptors. Conclusion:Quercetin shows the inhibitory or inducing effect on a variety of drug-metabolizing enzymes, therefore, it can interact with other drugs.

Phenoconversion of drug-metabolizing enzymes and its mechanism during inflammatory conditions / 国际药学研究杂志

Inflammatory conditions are associated with most diseases. Phenoconversion of drug-metabolizing enzymes (DME) leads to altered drug metabolism and disposition. It has profound impact on the pharmacotherapy of widely used clinically relevant medications in terms of safety and efficacy. More and more evidence has proved that elevated levels of proinflammatory cytokines may downregulate the expression and the activity of many Phase I and Phase “DME, which are involved in complex regulation mechanisms of drug disposition. The aim of this review is to present the recent findings in this area. Clinical practice based on personalized medicine according to DME phenotype with improved safety and efficiency can yield robust efficacy outcomes of drug treatment and has promising future prospects.

Mass spectrometry-based protein quantification and its application in pharmacokinetic research / 中国药科大学学报

@#Quantitative proteomics is a mass spectrometry-based toolkit used to analyze and quantify entire proteins contained in whole cells, tissues or organisms. It has become an increasingly important element in exploring the mechanism of various biological processes such as discovering novel biomarkers and unknown drug targets. Emerging advances in biological mass spectrometry instrumentation and data acquisition methodologies have provided a state-of-the-art platform for protein quantification, prompting the research of proteomics evolving from the simple qualitative to the accurate quantitative approach. This review aims to introduce the most recent advancements in mass spectrometry instrumentation and methodologies of data acquisition, focusing on their characteristics and applying fields. It also highlights several significant applications of biological mass spectrometry in pharmaceutical research such as quantifitation of drug transporters and metabolizing enzymes, and pharmacokinetic study of therapeutic peptides and proteins.

Phenoconversion of drug-metabolizing enzymes and its mechanism during inflammatory conditions / 国际药学研究杂志

Inflammatory conditions are associated with most diseases. Phenoconversion of drug-metabolizing enzymes(DME) leads to altered drug metabolism and disposition. It has profound impact on the pharmacotherapy of widely used clinically relevant medications in terms of safety and efficacy. More and more evidence has proved that elevated levels of proinflammatory cytokines may downregulate the expression and the activity of many Phase Ⅰ and Phase Ⅱ DME, which are involved in complex regulation mechanisms of drug disposition. The aim of this review is to present the recent findings in this area. Clinical practice based on personalized medicine according to DME phenotype with improved safety and efficiency can yield robust efficacy outcomes of drug treatment and has promising future prospects.

Distribution of genetic polymorphisms of genes encoding drug metabolizing enzymes & drug transporters - a review with Indian perspective.

Phase I and II drug metabolizing enzymes (DME) and drug transporters are involved in the absorption, distribution, metabolism as well as elimination of many therapeutic agents, toxins and various pollutants. Presence of genetic polymorphisms in genes encoding these proteins has been associated with marked inter-individual variability in their activity that could result in variation in drug response, toxicity as well as in disease predisposition. The emergent field pharmacogenetics and pharmacogenomics (PGx) is a promising discipline, as it predicts disease risk, selection of proper medication with regard to response and toxicity, and appropriate drug dosage guidance based on an individual’s genetic make-up. Consequently, genetic variations are essential to understand the ethnic differences in disease occurrence, development, prognosis, therapeutic response and toxicity. For that reason, it is necessary to establish the normative frequency of these genes in a particular population before unraveling the genotype-phenotype associations. Although a fair amount of allele frequency data are available in Indian populations, the existing pharmacogenetic data have not been compiled into a database. This review was intended to compile the normative frequency distribution of the variants of genes encoding DMEs (CYP450s, TPMT, GSTs, COMT, SULT1A1, NAT2 and UGTs) and transporter proteins (MDR1, OCT1 and SLCO1B1) with Indian perspective.

Effects of Buyang Huanwu Decoction on antioxidant and drug-metabolizing enzymes in rat liver / 中国天然药物

AIM@#To study the effect of Buyang Huanwu Decoction (BYHWD) on the antioxidant enzymes and drug-metabolizing enzymes in rat liver.@*METHOD@#Following treatment of rats with BYHWD at 6.42, 12.83, or 25.66 g·kg(-1) per day for 15 days, microsomes and cytosols isolated from the liver tissues were prepared by differential centrifugation according to standard procedures. The activities of the antioxidant enzymes and cytochrome b5, NADPH-cytochrome P450 reductase, CYP3A, CYP2E1, UGT, and GST of the rat livers were determined by UV-Vis spectrophotometer.@*RESULTS@#The activities of ALT, AST, antioxidant enzymes, and the Hepatosomatic Index in serum were not significantly affected. In cytosols, the activity of CAT was significantly increased at the dosage of 12.83 g·kg(-1), and all the other antioxidant activities and MDA levels were not affected by this treatment. BYHWD had no effect on cytochrome b5, NADPH-cytochrome P450 reductase, CYP3A, and UGT. At the highest dose (25.66 g·kg(-1)), the activity of CYP2E1 was significantly inhibited, and the activities of GST and the level of GSH were increased.@*CONCLUSION@#BYHWD is safe for the liver, and has the functions of detoxification and antioxidant. Patients should be cautioned about the herb-drug interaction of BYHWD and CYP2E1 substrates.

Genetic polymorphisms of drug-metabolizing enzymes CYP2C19,NAT2, and TPMT in a Han Chinese population from He-nan area / 中国新药与临床杂志

AIM: To determine the distribution and frequency of functionally important allelic variants in the cytochromes P450 (CYP) 2C19, arylamine N-acetyltransferase 2 (NAT2), and thiopurine S-methyltransferase (TPMT) genes in the Han Chinese population and compare them with those of other ethnic populations.METHODS: Genotyping was carried out in a total of 210 unrelated Han Chinese volunteers derived from He-nan area. CYP2C19 variants ( * 2 and * 3), NAT2 variants ( * 6 and * 7), and TPMT variants ( * 3A, * 3B, and * 3C) were detected using polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP)assays. Detection of NA T2 * 5 and TPMT * 2 were performed using allele-specific polymerase chain reaction assays. RESULTS: Allele frequencies of CYP2C19 * 2 and * 3 occurred with 34.76 % and 6.4 %, respectively.Thirty-one persons ( 14.8 % ) carried two of these CYP2C19 alleles responsible for poor metabolizing activity.The frequencies of specif ic NAT2 alleles were 59.1%, 4.1%, 26.4 %, and 9.5 % for * 4 (wild-type), * 5(341C), * 6 (590A), and * 7 (857A), respectively. Genotyping of three different single nucleotide polymorphisms in the NA T2 gene revealed that the frequency of slow acetylators was 19.5 %. TPMT * 3C had an allelic frequency of 1.2 %. TPMT* 2, TPMT * 3A, or TPMT* 3B was not detected in the analysed samples. CONCLUSION: The overview of allele distribution for drug-metabolizing enzymes CYP2C19, NAT2, and TPMT among a Han Chinese population shows obvious difference to Caucasians. The data will be useful for clinical pharmacokinetic investigation and drug dosage administration to Han Chinese population.

Alterations of maternal hepatic drug-metabolizing and antioxidative enzymes in tobacco-induced intrauterine growth retardation in rats / 中国临床药理学与治疗学

AIM: To evaluate the alterations of maternal hepatic drug-metabolizing enzymes and antioxidative function in tobacco-induced intrauterine growth retardation (IUGR). METHODS:Pregnant rats were assigned to control group and tobacco group. IUGR model was produced by smoking from gestational days (GD) 9 to GD 20. Fetuses were removed by laparotomy on GD 21. The fetal development parameters such as fetal body weights, litter size and placental weights were recorded. Subcelluar fractions of liver were prepared by differential centrifugation. Activities of drug-metabolizing and antioxidative enzymes were monitored. RESULTS:In the tobacco exposure group, fetal body weights, litter size and placental weights were significantly reduced (P

Changes of liver xenobiotic-metabolizing function at different status of hepatic injury / 中国药理学通报

Aim The changes and characteristics of liver drug-metabolizing and antioxiditive functions in different status of hepatic injury was investigated to provide support for clinical drug treatments in hepatic fibrosis. Methods Carbon tetrachloride (CCl 4) and other mixture factors were used to make animal model of acute hepatic injury, hepatic fibrosis and cirrhosis, respectively. Subcelluar fractions of liver were prepared by differential centrifugation. Activities of drug-metabolizing and antioxidative enzymes were monitored. Results Levels of phase I enzymes-cytochrome P450 (CYP), CYP1A1 (7-ethoxyresorufin O-deethylation), CYP2E1 (aniline hydroxylation), CYP3A1/2 (erythromycin N-demethylation), and phase Ⅱ enzymes-glutathione S-transferase (GST) were reduced remarkably in hepatic microsomes in different hepatic injury status in a time-dependent manner. However, the activity of CYP2E1 came to be the lowest in acute hepatic injury and recovered gradually when injury time was prolonged. In hepatic fibrosis, the activities of CYP1A,CYP2E1,CYP3A and GST reached 68%,56%,81% and 59%, respectively, of the control, and the functions of antioxidative enzymes in cytosol GST,catalase(Cat) and glutathione peroxidase(GSH-Px) declined to 85%,76% and 54%, respectively, of the control. Conclusion The xenobiotic-metabolizing abilities in liver with hepatic fibrosis were distinctly decreased, which constantly relates with the degrees and the lengths of hepatic injury.

Genetic polymorphism of enzymes involved in xenobiotic metabolism and the risk of lung cancer

Chronic inhalation of cigarette smoke is a major risk factor for the development of lung cancer. It has been suggested that genetic susceptibility may contribute to the risk, because only a small portion of smokers develops the disease. Several polymorphisms that involve the metabolic activation or detoxification of carcinogens derived from cigarette smoke have been found to be associated with lung cancer risk. Many studies have focused on the relation between the distribution of polymorphic variants of different forms of the metabolic enzymes and lung cancer susceptibility. In this respect two groups of genetic polymorphisms of enzymes involved in xenobiotic metabolism, cytochrome P450 (CYP) and glutathione S-transferases (GSTs), have been discussed.CYP multigene superfamily consists of 10 subfamilies (CYP1-CYP10). A positive association between development of lung cancer and the mutant homozygous genotype ofCYP1A1 gene has been reported in several Japanese populations but such an association has not been observed in either Caucasians or African-Americans. The relation betweenCYP2D6 and lung cancer remains conflicting and inconclusive. Several polymorphisms have been identified at theCYP2E1 locus. No definitive link between the polymorphisms ofCYP2E1 and the risk of lung cancer has, however, been identified. The role of otherCYP2 isoforms in lung carcinogenesis has not been sufficiently investigated.GSTs form a superfamily of genes consisting of five distinct families, namedGSTA, GSTM, GSTP, GSTT andGSTS. The role ofGSTM, GSTT1 orGSTP1 polymorphism in modifying the lung cancer risk may be more limited than has been so far anticipated.Although some genetic polymorphisms discussed here have not shown significant increases/decreases in risk, individuals with differing genotypes may have different susceptibilities to lung cancer. Hopefully, in future studies it will be possible to screen for lung cancer using specific biomarkers.

Genetic Polymorphism of Enzymes Involved in Xenobiotic Metabolism and the Risk of Lung Cancer

Chronic inhalation of cigarette smoke is a major risk factor for the development of lung cancer. It has been suggested that genetic susceptibility may contribute to the risk, because only a small portion of smokers develops the disease. Several polymorphisms that involve the metabolic activation or detoxification of carcinogens derived from cigarette smoke have been found to be associated with lung cancer risk. Many studies have focused on the relation between the distribution of polymorphic variants of different forms of the metabolic enzymes and lung cancer susceptibility. In this respect two groups of genetic polymorphisms of enzymes involved in xenobiotic metabolism, cytochrome P450 (CYP) and glutathione S-transferases (GSTs), have been discussed. CYP multigene superfamily consists of 10 subfamilies (CYP1-CYP10). A positive association between development of lung cancer and the mutant homozygous genotype of CYP1A1 gene has been reported in several Japanese populations but such an association has not been observed in either Caucasians or African-Americans. The relation between CYP2D6 and lung cancer remains conflicting and inconclusive. Several polymorphisms have been identified at the CYP2E1 locus. No definitive link between the polymorphisms of CYP2E1 and the risk of lung cancer has, however, been identified. The role of other CYP2 isoforms in lung carcinogenesis has not been sufficiently investigated. GSTs form a superfamily of genes consisting of five distinct families, named GSTA, GSTM, GSTP, GSTT and GSTS. The role of GSTM, GSTT1 or GSTP1 polymorphism in modifying the lung cancer risk may be more limited than has been so far anticipated.Although some genetic polymorphisms discussed here have not shown significant increases/decreases in risk, individuals with differing genotypes may have different susceptibilities to lung cancer. Hopefully, in future studies it will be possible to screen for lung cancer using specific biomarkers.

Effects of Active Hexose Correlated Compounds on Drug Induced Liver Injury in Mice

AHCC (Active Hexose Correlated Compounds), which was at first extracted from cultured broth of Basidiomycotina, is known to be one of the Biological Response Modifiers (BRM). We examined the protective effects of AHCC on carbon tetrachloride (CCl4) and thioacetamide (TAA)-induced liver injury in mice. The AHCC pretreatment prevented the suppression of several physiological and biochemical parameters in the mice injected with CCl4 or TAA for 5 days. The liver weights and serum ALT and AST levels were increased by CCl4 or TAA, the degree of which was significantly reduced with the AHCC pretreatment. The AHCC pretreatment induced increasing activity of GST (glutathione s-transferase) and showed an increasing tendency of P450 and EROD (ethoxyresorufin o-dealkylation). The AHCC pretreatment also showed negative effects against the suppression of drug metabolizing enzymes, such as P450, EROD, and GST induced by CCl4 or TAA. AHCC pretreatment showed protective effects with significant inhibition of fatty change, inflammation, and necrosis in CCl4 and TAA intoxicated mice liver. The present study suggests that the protective effect of AHCC pretreatment might be related to the protection of liver from the drug induced liver injury in mice model.