{"title":"Deciphering Key Interactions of Ligands with CYP3A4-Template* system.","authors":"Yasushi Yamazoe, Takashi Yamada, Akihiko Hirose, Norie Murayama","doi":"10.14252/foodsafetyfscj.D-20-00023","DOIUrl":"https://doi.org/10.14252/foodsafetyfscj.D-20-00023","url":null,"abstract":"<p><p>Cytochrome P450 (CYP)-mediated metabolisms are often associated with biological and toxicological events of chemicals. A major hepatic enzyme, CYP3A4, showed clear distinctions on their catalyses even among ligands having resemble structures. To better understand mechanisms of their distinct catalyses, possible associations of ligand interactions at specific parts of CYP3A4 residues were investigated using CYP3A4-Template system developed (DMPK 2019 and 2020). A placement was available selectively for CYP3A4-mediated R-thalidomide 5-oxidation on Template, but not for the 5'-oxidation and the S-isomer oxidations. Similar placements were generated for pomalidomide (4-amino-thalidomide), but not for a poor ligand, lenalidomide (3-deoxy-pomalidomide). The latter ligand took placements lacking IJK-Interaction or sticking the 4-amino part beyond the facial-side wall on Template. A placement was available for the <i>tert</i>-butyl oxidation of terfenadine, but not for an analog, ebastine. Their interactions with upper-Cavity-2 residue were expected to differ at their sites of oxygen substituents. Some phenolic antioxidants behave distinctly toward biological oxidations <i>in vitro</i> and <i>in vivo</i>. Butylated hydroxytoluene is oxidized to the peroxy-derivative <i>in vitro</i>, but solely to the oxidized metabolites at the benzyl and <i>tert</i>-butyl methyl positions <i>in vivo</i>. Involvement of CYP3A4 were suggested for all the three reactions from the placements on Template. Tocopherols were also applied on Template for the oxidations for chroman and side-chain terminals. The primary placement was suggested to undergo the futile-recycling through formation of the peroxide intermediate subsequently to lead the substantial lack of the CYP3A4-mediated oxidation. These data suggest the effectiveness of CYP3A4-Template assessment to understand the causal basis of poor oxidations and also to verify the <i>in vivo</i> contribution of CYP3A4-mediated peroxidative reactions.</p>","PeriodicalId":73044,"journal":{"name":"Food safety (Tokyo, Japan)","volume":"9 1","pages":"10-21"},"PeriodicalIF":0.0,"publicationDate":"2021-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25536251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Food safety (Tokyo, Japan)Pub Date : 2021-02-10eCollection Date: 2021-03-01DOI: 10.14252/foodsafetyfscj.D-20-00018
Takahiro Watanabe, Rieko Matsuda, Chikako Uneyama
{"title":"Probabilistic Estimation of Dietary Intake of Methylmercury from Fish in Japan.","authors":"Takahiro Watanabe, Rieko Matsuda, Chikako Uneyama","doi":"10.14252/foodsafetyfscj.D-20-00018","DOIUrl":"https://doi.org/10.14252/foodsafetyfscj.D-20-00018","url":null,"abstract":"Abstract Dietary intake of methylmercury from fish was estimated via Monte Carlo simulation using data for methylmercury concentrations in 210 fish samples and data regarding fish consumption extracted from the Japanese National Health and Nutrition Survey. The fish analyzed were classified into 5 groups according to categories used in the survey. The distribution of consumption of fish from each group was used without fitting to statistical distributions. A log-normal distribution was fitted to the distribution of methylmercury concentration in each fish group. Two random numbers that followed these distributions were generated, and a trial value was calculated by multiplying these random numbers. The trial value was divided by the body weight (50 kg) to arrive at an estimate of dietary methylmercury intake. A total of 100,000 Monte Carlo simulation iterations were performed. The estimated mean daily intake of methylmercury was 0.093 µg/kg body weight (bw)/day. This value is well below the tolerable daily intake of 0.292 µg/kg bw/day calculated from the tolerable weekly intake (2.0 µg/kg bw/week) established by the Food Safety Commission of Japan. The probability that the daily intake of methylmercury exceeds the tolerable daily intake was 7.6%. As there are no data regarding fish consumption for consecutive days, estimation of the weekly intake of methylmercury is a subject for future studies.","PeriodicalId":73044,"journal":{"name":"Food safety (Tokyo, Japan)","volume":"9 1","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2021-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25536250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Continuous Estimation of Annual Committed Effective Dose of Radioactive Cesium by Market Basket Study in Japan from 2013 to 2019 after Fukushima Daiichi Nuclear Power Plant Accident.","authors":"Hiromi Nabeshi, Tomoaki Tsutsumi, Masataka Imamura, Yoshinori Uekusa, Akiko Hachisuka, Rieko Matsuda, Reiko Teshima, Hiroshi Akiyama","doi":"10.14252/foodsafetyfscj.D-20-00017","DOIUrl":"https://doi.org/10.14252/foodsafetyfscj.D-20-00017","url":null,"abstract":"<p><p>Radionuclide contamination in foods has been a great concern after the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident. To estimate time trends of daily intake and annual committed effective dose of radionuclides after the accident, radioactive cesium (r-Cs; <sup>134</sup>Cs and <sup>137</sup>Cs) and potassium-40 (<sup>40</sup>K) in market basket (MB) samples prepared at 6-month intervals in periods from September 2013 to March 2019 in 15 regions of Japan were analyzed using γ-ray spectrometry. The annual committed effective dose of r-Cs, calculated at non-detected radionuclide levels assumed to be half the limit of detection (LOD), appeared to decrease gradually in 11 regions close to the FDNPP that were more likely to be affected by the accident. Differences in doses among the 15 regions were large just after the accident, but gradually decreased. In particular, <sup>134</sup>Cs has not been detected in any MB sample in any region since September 2018, and annual committed effective dose from <sup>134</sup>Cs in all regions was mostly constant at around 0.3 μSv/year (given the respective LODs). The maximum annual committed effective dose of r-Cs in this study was decreased from 2.7 μSv/year in September 2013 to 1.0 μSv/year in March 2019. In contrast, the range of annual committed effective dose of <sup>40</sup>K varied from approximately 150 to 200 μSv/year during that time frame and did not change much throughout the period of this study. Although annual committed effective doses of r-Cs in regions close to the FDNPP appeared to be higher than in regions far from the FDNPP, doses in all regions are remaining at a much lower levels than the intervention exemption level, 1 mSv/year, in foods in Japan.</p>","PeriodicalId":73044,"journal":{"name":"Food safety (Tokyo, Japan)","volume":"8 4","pages":"97-114"},"PeriodicalIF":0.0,"publicationDate":"2020-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38791796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Food safety (Tokyo, Japan)Pub Date : 2020-12-25eCollection Date: 2020-12-01DOI: 10.14252/foodsafetyfscj.D-20-00007
Yoshinari Suzuki, Noriko Tanaka, Hiroshi Akiyama
{"title":"Attempt of Bayesian Estimation from Left-censored Data Using the Markov Chain Monte Carlo Method: Exploring Cr(VI) Concentrations in Mineral Water Products.","authors":"Yoshinari Suzuki, Noriko Tanaka, Hiroshi Akiyama","doi":"10.14252/foodsafetyfscj.D-20-00007","DOIUrl":"10.14252/foodsafetyfscj.D-20-00007","url":null,"abstract":"<p><p>Hexavalent chromium (Cr(VI)) is toxic, carcinogenic, and mutagenic substances. Oral exposure to Cr(VI) is thought to be primarily from drinking water. However, under the certain reporting limit (~0.1 µg/L), percentage of Cr(VI) concentration in mineral water products under the reporting limit were estimated higher than 50%. Data whose values are below certain limits and thus cannot be accurately determined are known as left-censored. The high censored percentage leads to estimation of Cr(VI) exposure uncertain. It is well known that conventional substitution method often used in food analytical science cause severe bias. To estimate appropriate summary statistics on Cr(VI) concentration in mineral water products, parameter estimation using the Markov chain Monte Carlo (MCMC) method under assumption of a lognormal distribution was performed. Stan, a probabilistic programming language, was used for MCMC. We evaluated the accuracy, coverage probability, and reliability of estimates with MCMC by comparison with other estimation methods (discard nondetects, substituting half of reporting limit, Kaplan-Meier, regression on order statistics, and maximum likelihood estimation) using 1000 randomly generated data subsets (<i>n</i> = 150) with the obtained parameters. The evaluation shows that MCMC is the best estimation method in this context with greater accuracy, coverage probability, and reliability over a censored percentage of 10-90%. The mean concentration, which was estimated with MCMC, was 0.289×10<sup>-3</sup> mg/L and this value was sufficiently lower than the regulated value of 0.05 mg/L stipulated by the Food Sanitation Act.</p>","PeriodicalId":73044,"journal":{"name":"Food safety (Tokyo, Japan)","volume":"8 4","pages":"67-89"},"PeriodicalIF":0.0,"publicationDate":"2020-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38789894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Food safety (Tokyo, Japan)Pub Date : 2020-12-25eCollection Date: 2020-12-01DOI: 10.14252/foodsafetyfscj.D-20-00031
{"title":"Deoxynivalenol and Nivalenol (2nd edition) [Assuring the Maximum Level of Deoxynivalenol in Wheat] (Natural Toxins and Mycotoxins).","authors":"","doi":"10.14252/foodsafetyfscj.D-20-00031","DOIUrl":"https://doi.org/10.14252/foodsafetyfscj.D-20-00031","url":null,"abstract":"<p><p>Food Safety Commission of Japan (FSCJ) was requested by the Ministry of Health, Labour and Welfare (MHLW) to conduct a risk assessment of deoxynivalenol (DON) to assure the maximal level for DON in foods. Previously, FSCJ had conducted a self-tasking risk assessment of DON and nivalenol (NIV) in 2010. In the current 2nd edition, only the assessment of DON has been revised. Grains contaminated with DON may be also contaminated with its derivatives, namely, 3-acetyldeoxynivalenol (3-Ac-DON), 15-acetyldeoxynivalenol (15-Ac-DON) and deoxynivalenol-3-glucoside (DON-3-glucoside). However, these substances orally ingested are rapidly biotransformed into DON. Therefore, FSCJ identified the total DON (sum of DON and its derivatives) to be assessed. The toxicity of DON was assessed based on the data of absorption-distribution-metabolism-excretion (ADME), acute toxicity, sub-acute toxicity, chronic toxicity, carcinogenicity, reproductive/developmental toxicity, genotoxicity, and immunotoxicity. DON was considered to have no significant genotoxic activity <i>in vivo</i>. The no-observed-adverse-effect level (NOAEL), based on the two-year chronic toxicity study in mice, was set at 0.1 mg DON/kg bw/day. By applying an uncertainty factor (UF) of 100, the TDI for DON was determined as 1 µg /kg bw/day. The average estimated exposure levels of total DON were 0.09 µg /kg bw/day and 0.22 µg/kg bw/day in the whole population and the 1-6 years group, respectively, by the Monte-Carlo method. The average exposure level in Japan was thus judged to be below the TDI, although a chance to exceed the TDI remains possible in the 1-6 years group depending on eating habits and DON contamination. For NIV, the genotoxic property was not able to be assessed due to the limited availability of the experimental data. No carcinogenic effect was observed in a two-year chronic toxicity study in mice, and the International Agency for Research on Cancer (IARC) also classifies <i>Fusarium</i> spp toxins including NIV to be in group 3. FSCJ thus judged that TDI can be set for NIV. Based on various toxicity studies, the TDI of NIV was determined at 0.4 µg/kg bw/day by taking into account of LOAEL 0.4 mg NIV/kg bw/day in a subacute toxicity study in rats with 90-day oral administration and UF of 1,000. The exposure level of NIV in Japan was estimated to be below the TDI. FSCJ judged it's unlikely that NIV intake leads to adverse health effects in general population.</p>","PeriodicalId":73044,"journal":{"name":"Food safety (Tokyo, Japan)","volume":"8 4","pages":"115-117"},"PeriodicalIF":0.0,"publicationDate":"2020-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38791797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Changes in the Risk Perception of Food Safety between 2004 and 2018.","authors":"Aiko Abe, Kazuo Koyama, Chie Uehara, Azusa Hirakawa, Itsuko Horiguchi","doi":"10.14252/foodsafetyfscj.D-20-00015","DOIUrl":"https://doi.org/10.14252/foodsafetyfscj.D-20-00015","url":null,"abstract":"<p><p>To afford the future agenda of risk communication through an evaluation of the past, we examined the changes in risk perception in the food safety sector over the 15 years (2004-2018) since the establishment of the Food Safety Commission of Japan (FSCJ) in 2003 by analyzing the data of the food safety monitor survey. Hazards such as contaminants including cadmium, methylmercury and arsenic, and pesticide residues caused high levels of concern among the public in 2004. In contrast, hazards such as food poisoning by harmful microorganisms and so-called \"Health foods\" have been ranked high among concerns since 2008 and 2014, respectively. Scoring of concern levels showed that concern related to food additives and pesticide residues intentionally added to foods and controlled has gradually decreased in a time-dependent manner. These concern scores were considerably lower in male monitors than in female ones; the scores were also lower for individuals with professional experience in the food sector than without the experience. The concern scores for contaminants were lower for males with professional experience. The concern scores related to food poisoning and health foods were not decreased and were remained high in recent years. These scores did not show clear dependence on job experience or gender of the monitors. A gap between food specialists and other attributes in the basic recognition of risk seems to make it difficult to communicate effectively and constructively among various interested individuals. To improve the quality of risk communication in the food safety field, it will be necessary to provide scientific knowledge and information regarding food safety management mechanisms for individuals without professional experience in the food sector, taking into account the changes in information media and influence on risk perception.</p>","PeriodicalId":73044,"journal":{"name":"Food safety (Tokyo, Japan)","volume":"8 4","pages":"90-96"},"PeriodicalIF":0.0,"publicationDate":"2020-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38789895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Risk Management Knowledges about Oysters for Raw Consumption and Norovirus.","authors":"Kazuo Koyama, Azusa Hirakawa, Chie Uehara, Itsuko Horiguchi","doi":"10.14252/foodsafetyfscj.D-20-00014","DOIUrl":"10.14252/foodsafetyfscj.D-20-00014","url":null,"abstract":"<p><p>This study used questionnaires to evaluate knowledge levels of risk management of raw-consumption of oysters and of norovirus as health hazards among monitors signed up for Food Safety Commission of Japan (FSCJ) having work experiences in food fields. The mean scores of monitors on norovirus knowledge were relatively high (79%), but on oyster raw-consumption were low (64%). Scores varied depending on occupational experiences; highest among administrative officials, high among researchers in food companies, and low among medical workers and educators. The higher scores with more practical experiences for risk management of oyster raw-consumption and norovirus were observed among the monitors. These monitors were expected better to recognize the risks, wheres only few monitors among the opinion-leaders replied correctly to all the questions. These results suggest the need of improvement on the management system for oyster raw-consumption, from the current complicated to the more precise and reinforced for consumers. To efficiently manage the risk associated with the consumption of raw oysters, the government should provide more relevant information of risk management to persons having interest, particularly influencers, in order to disseminate information and to improve knowledge among cooks and consumers.</p>","PeriodicalId":73044,"journal":{"name":"Food safety (Tokyo, Japan)","volume":"8 3","pages":"59-63"},"PeriodicalIF":0.0,"publicationDate":"2020-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38545999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Food safety (Tokyo, Japan)Pub Date : 2020-09-25eCollection Date: 2020-09-01DOI: 10.14252/foodsafetyfscj.D-20-00019
{"title":"Cattle Meat and Offal Imported from the United States of America, Canada and Ireland to Japan (Prions).","authors":"","doi":"10.14252/foodsafetyfscj.D-20-00019","DOIUrl":"https://doi.org/10.14252/foodsafetyfscj.D-20-00019","url":null,"abstract":"<p><p>Food Safety Commission of Japan (FSCJ) was requested by the Ministry of Health, Labour and Welfare (MHLW) to conduct a risk assessment of cattle meat and offal imported from the United States of America (U.S.A.), Canada and Ireland. FSCJ assessed potential influences on bovine spongiform encephalopathy (BSE) risks to human health in cases of the alteration of cattle age to be allowed to import of cattle meat and offal from the three countries, from the current under 30 months of age to no age limitation, in line with the international standards for mitigating BSE risks. FSCJ judges that the control measures regarding \"risks related to slaughtering and meat processing\" are appropriately implemented in the three countries. FSCJ concludes that potential variations of BSE risks to human health by removing the age limit on cattle meat and offal excluding specified risk material (SRMs) imported from the three countries in line with the international standards is negligible.</p>","PeriodicalId":73044,"journal":{"name":"Food safety (Tokyo, Japan)","volume":"8 3","pages":"64-65"},"PeriodicalIF":0.0,"publicationDate":"2020-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38546000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Elution of Radioactive Cesium from Tofu by Water Soaking.","authors":"Mitsuru Yoshida, Hitomi Kaino, Saori Shidara, Kazuhiro Chiku, Mayumi Hachinohe, Shioka Hamamatsu","doi":"10.14252/foodsafetyfscj.D-20-00011","DOIUrl":"https://doi.org/10.14252/foodsafetyfscj.D-20-00011","url":null,"abstract":"<p><p>Elution of cesium-137 (<sup>137</sup>Cs) from tofu into water was investigated to know the behavior of <sup>137</sup>Cs during preservation and cooking. The food processing retention factor (<i>Fr</i>) reached 0.55 when tofu was soaked in water at a ratio of 1:2 <i>w</i>/<i>w</i> for 24 h at 4°C. Doubling the amount of water did not further significantly decrease <i>Fr</i>. When tofu was held in water at a ration of 1:2 w/w at a temperature of 80℃ for 50 min, <i>Fr</i> was 0.72. Increasing the amount of water to 10 times the tofu weight did not further reduce <i>Fr</i> significantly. Cesium-137 is mostly bound to tofu and does not freely diffuse into water. Tofu was then soaked in water at a ratio of 1:2 w/w at 4℃ for 24 h, placed in new water at a ratio of 1:2 w/w, and held at 80℃ for 50 min, resulting in an <i>Fr</i> 0.33. This value is close to an estimated <i>Fr</i> calculated by multiplying the <i>Fr</i> of 0.55 from soaking at 4°C by the <i>Fr</i> of 0.72 from the hot water treatment. The calculated <i>Fr</i> from soybeans sequentially processing into tofu, soaking tofu at 4°C for 24 h and in hot water at 80°C for 50 min was about 0.1, indicating 90% removal of <sup>137</sup>Cs. Degree of decrease in <sup>137</sup>Cs during preservation and cooking of tofu demonstrated in this study will be useful for exposure assessment of <sup>137</sup>Cs through oral intake of contaminated soybeans after processing and cooking.</p>","PeriodicalId":73044,"journal":{"name":"Food safety (Tokyo, Japan)","volume":"8 3","pages":"55-58"},"PeriodicalIF":0.0,"publicationDate":"2020-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38545998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Food safety (Tokyo, Japan)Pub Date : 2020-06-26eCollection Date: 2020-06-01DOI: 10.14252/foodsafetyfscj.D-20-00010
Yasushi Yamazoe, Takashi Yamada, Kiyoshi Nagata
{"title":"Prediction and Characterization of CYP3A4-mediated Metabolisms of Azole Fungicides: an Application of the Fused-grid Template* system.","authors":"Yasushi Yamazoe, Takashi Yamada, Kiyoshi Nagata","doi":"10.14252/foodsafetyfscj.D-20-00010","DOIUrl":"10.14252/foodsafetyfscj.D-20-00010","url":null,"abstract":"<p><p>Human CYP3A4 is involved in metabolisms of diverse hydrophobic chemicals. Using the data of therapeutic azole fungicides known to interact with CYP3A4, applicability of CYP3A4 Template system was first confirmed to reconstitute faithfully the interaction on Template. More than twenty numbers of pesticide azoles were then applied to the Template system. All the azole stereo-isomers applied, except for talarozole, interacted through nitrogen atoms of triazole or imidazole parts and sat stably for inhibitions through fulfilling three-essential interactions. For their CYP3A4-mediated oxidations, clear distinctions were suggested among the enantiomers and diastereomers of azole pesticides on Templates. Thus, the stereoisomers would have their-own regio- and stereo-selective profiles of the metabolisms. A combined metabolic profile of each azole obtained with CYP3A4 Template system, however, resembled with the reported profile of the <i>in vivo</i> metabolism in rats. These results suggest the major roles of CYP3A forms on the metabolisms of most of azole pesticides in both rats and humans. Free triazole is a metabolite of azole fungicides having a methylene-spacer between triazole and the rest of the main structures in experimental animals and humans. During the simulation experiments, a placement for the oxidation of a methylene spacer between the triazole and main carbon-skeleton was found to be available throughout the azole fungicides tested on Template. The occurrence of this reaction to lead to triazole-release is thus discussed in relation to the possible involvement of CYP3A forms.</p>","PeriodicalId":73044,"journal":{"name":"Food safety (Tokyo, Japan)","volume":"8 2","pages":"34-51"},"PeriodicalIF":0.0,"publicationDate":"2020-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38120464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}