DRUG METABOLISM AND DISPOSITION
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2020
·Vol. 48
·期 5
·345-352
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IF 3.231
Xiaohua Zhao,Hong Ma,Qiusha Pan,Haiyi Wang,Xingkai Qian,Peifang Song,Liwei Zou,Mingqing Mao,Shuyue Xia,Guangbo Ge,Ling Yang
Doxophylline (DOXO) and theophylline are widely used as bronchodilators for treating asthma and chronic obstructive pulmonary disease, and DOXO has a better safety profile than theophylline. How DOXO’s metabolism and disposition affect its antiasthmatic efficacy and safety remains to be explored. In this study, the metabolites of DOXO were characterized. A total of nine metabolites of DOXO were identified in vitro using liver microsomes from human and four other animal species. Among them, six metabolites were reported for the first time. The top three metabolites were theophylline acetaldehyde (M1), theophylline-7-acetic acid (M2), and etophylline (M4). A comparative analysis of DOXO metabolism in human using liver microsomes, S9 fraction, and plasma samples demonstrated the following: 1) The metabolism of DOXO began with a cytochrome P450 (P450)–mediated, rate-limiting step at the C ring and produced M1, the most abundant metabolite in human liver microsomes. However, in human plasma, the M1 production was rather low. 2) M1 was further converted to M2 and M4, the end products of DOXO metabolism in vivo, by non-P450 dismutase in the cytosol. This dismutation process also relied on the ratio of NADP+/NADPH in the cell. These findings for the first time elucidated the metabolic sites and routes of DOXO metabolism in human.
研究领域:
药理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Heng Du,Xu Liu,Jianghua Shen,Hailong Yuan,Hao Zhang,Gan Xi,Yujing Li,Yuhan Wang,Jiahe Zhang,Chaofan Yang,Pengfei Xu,Jiawan Wang,Fang Wang,Siqi Liu,Yanan Zhou,Qi Gu,Jingjing Lu,Tuo Wei,Zeyu Gao,Jingyi Zang,Jun Wang,Moshi Song
Myocardial ischemia/reperfusion (I/R) injury is a major contributor to myocardial damage, leading to adverse cardiac remodeling and dysfunction. Recent studies have highlighted the potential of gut microbiota-derived metabolites in modulating cardiac outcomes. Here, the cardioprotective effects of a commensal bacterium Flavonifractor plautii ( F. plautii ) and its metabolite desaminotyrosine (DAT) against myocardial I/R injury are investigated. We showed that prophylactic gavage of F. plautii attenuates myocardial I/R injury as evidenced by improved cardiac function and reduced cardiac injury. We also found that its metabolite DAT recapitulates these cardioprotective effects against myocardial I/R injury. Transcriptomic analysis has revealed that DAT preserves cardiac tissue and attenuates immune responses against myocardial I/R injury. Mechanistically, DAT promotes cardiomyocyte survival through the modulation of the nicotinamide adenine dinucleotide phosphate (NADP + /NADPH) ratio. Further, DAT suppressed macrophage proinflammatory activities and cardiac inflammation via the reduction in interleukin-6 (IL-6) production. Taken together, our findings indicate that F. plautii and its metabolite DAT exert pleiotropic cardioprotective effects against myocardial I/R injury, suggesting them as potential prophylactic therapeutic options for alleviating myocardial I/R injury.
研究领域:
心脏病学
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微生物学
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药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-14
·
IF 14.7
Wei Xinlei,Yang Xue,Hu Congcong,Li Qiangzi,Liu Qianqian,Wu Yue,Xie Leipeng,Ning Xiao,Li Fei,Cai Tao,Zhu Zhiguang,Zhang Yi-Heng P. Job,Zhang Yanfei,Chen Xuejun,You Chun
In vitro biotransformation (ivBT) facilitated by in vitro synthetic enzymatic biosystems (ivSEBs) has emerged as a highly promising biosynthetic platform. Several ivSEBs have been constructed to produce poly-3-hydroxybutyrate (PHB) via acetyl-coenzyme A (acetyl-CoA). However, some systems are hindered by their reliance on costly ATP, limiting their practicality. This study presents the design of an ATP-free ivSEB for one-pot PHB biosynthesis via acetyl-CoA utilizing starch-derived maltodextrin as the sole substrate. Stoichiometric analysis indicates this ivSEB can self-maintain NADP + /NADPH balance and achieve a theoretical molar yield of 133.3%. Leveraging simple one-pot reactions, our ivSEBs achieved a near-theoretical molar yield of 125.5%, the highest PHB titer (208.3 mM, approximately 17.9 g/L) and the fastest PHB production rate (9.4 mM/h, approximately 0.8 g/L/h) among all the reported ivSEBs to date, and demonstrated easy scalability. This study unveils the promising potential of ivBT for the industrial-scale production of PHB and other acetyl-CoA-derived chemicals from starch.
研究领域:
生物技术
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生物化学
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合成生物学
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代谢工程
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）