scholarly journals Correction to The Structural Basis for Homotropic and Heterotropic Cooperativity of Midazolam Metabolism by Human Cytochrome P450 3A4

Biochemistry ◽  
2012 ◽  
Vol 51 (6) ◽  
pp. 1332-1332
Author(s):  
Arthur G. Roberts ◽  
Jing Yang ◽  
James R. Halpert ◽  
Sidney D. Nelson ◽  
Kenneth T. Thummel ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Structural Basis ◽  
Cytochrome P450 3A4 ◽  
Human Cytochrome ◽  
Midazolam Metabolism

scholarly journals The Structural Basis for Homotropic and Heterotropic Cooperativity of Midazolam Metabolism by Human Cytochrome P450 3A4

Biochemistry ◽  
2011 ◽  
Vol 50 (50) ◽  
pp. 10804-10818 ◽  
Author(s):  
Arthur G. Roberts ◽  
Jing Yang ◽  
James R. Halpert ◽  
Sidney D. Nelson ◽  
Kenneth T. Thummel ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Structural Basis ◽  
Cytochrome P450 3A4 ◽  
Human Cytochrome ◽  
Midazolam Metabolism

scholarly journals Structural basis for regiospecific midazolam oxidation by human cytochrome P450 3A4

2016 ◽  
Vol 114 (3) ◽  
pp. 486-491 ◽  
Author(s):  
Irina F. Sevrioukova ◽  
Thomas L. Poulos
Keyword(s):  
Crystal Structure ◽  
Cytochrome P450 ◽  
Active Site ◽  
Structural Information ◽  
Binding Mode ◽  
Structural Basis ◽  
Cytochrome P450 3A4 ◽  
Human Cytochrome ◽  
Cyp3a4 Substrate

Human cytochrome P450 3A4 (CYP3A4) is a major hepatic and intestinal enzyme that oxidizes more than 60% of administered therapeutics. Knowledge of how CYP3A4 adjusts and reshapes the active site to regioselectively oxidize chemically diverse compounds is critical for better understanding structure–function relations in this important enzyme, improving the outcomes for drug metabolism predictions, and developing pharmaceuticals that have a decreased ability to undergo metabolism and cause detrimental drug–drug interactions. However, there is very limited structural information on CYP3A4–substrate interactions available to date. Despite the vast variety of drugs undergoing metabolism, only the sedative midazolam (MDZ) serves as a marker substrate for the in vivo activity assessment because it is preferentially and regioselectively oxidized by CYP3A4. We solved the 2.7 Å crystal structure of the CYP3A4–MDZ complex, where the drug is well defined and oriented suitably for hydroxylation of the C1 atom, the major site of metabolism. This binding mode requires H-bonding to Ser119 and a dramatic conformational switch in the F–G fragment, which transmits to the adjacent D, E, H, and I helices, resulting in a collapse of the active site cavity and MDZ immobilization. In addition to providing insights on the substrate-triggered active site reshaping (an induced fit), the crystal structure explains the accumulated experimental results, identifies possible effector binding sites, and suggests why MDZ is predominantly metabolized by the CYP3A enzyme subfamily.

scholarly journals CO Binding Kinetics of Human Cytochrome P450 3A4

1995 ◽  
Vol 270 (10) ◽  
pp. 5014-5018 ◽  
Author(s):  
Aditya P. Koley ◽  
Jeroen T. M. Buters ◽  
Richard C. Robinson ◽  
Allen Markowitz ◽  
Fred K. Friedman
Keyword(s):  
Cytochrome P450 ◽  
Binding Kinetics ◽  
Cytochrome P450 3A4 ◽  
Human Cytochrome ◽  
Kinetics Of

scholarly journals Porcine foetal and neonatal CYP3A liver expression

2011 ◽  
Vol 1 (1) ◽  
pp. 1 ◽  
Author(s):  
Marie Louise Hiort Hermann ◽  
Mette Tingleff Skaanild
Keyword(s):  
Cytochrome P450 ◽  
Liver Microsomes ◽  
Cytochrome P450 3A4 ◽  
Chain Reaction ◽  
Hepatic Expression ◽  
Human Cytochrome ◽  
Foetal Liver ◽  
Polymerase Chain ◽  
Cyp3a Enzyme ◽  
Exogenous Substances

Human cytochrome P450 3A7 (CYP3A7) and cytochrome P450 3A4 (CYP3A4) are hepatic metabolising enzymes which participates in the biotransformation of endo- and exogenous substances in foetuses and neonates respectively. These CYP3A enzymes display an inverse relationship: CYP3A7 is the dominant enzyme in the foetal liver, whereas the expression of CYP3A4 is low. After parturition there is a shift in the expression, thus CYP3A7 is down regulated, while the level of CYP3A4 gradually increases and becomes the dominant metabolising CYP3A enzyme in the adult. The minipig is increasingly being used as a model for humans in biomedical studies, because of its many similarities with the human physiology and anatomy. The aim of this study was to examine whether, as in humans, a shift is seen in the hepatic expression of a CYP3A7- like enzyme to cytochrome P450 3A29 (CYP3A29) (an orthologue to the human CYP3A4) in minipigs. This was elucidated by examining the hepatic mRNA expression of CYP3A7 and CYP3A29 in 39 foetuses and newborn Göttingen minipigs using quantitative real time polymerase chain reaction (qPCR). Furthermore the immunochemical level of CYP3A7-LE and CYP3A29 was measured in liver microsomes using western blotting. The expression of CYP3A29 was approximately 9- fold greater in neonates compared to foetuses, and a similar difference was reflected on the immunochemical level. It was not possible to detect a significant level of foetal CYP3A7 mRNA, but immunoblotting showed a visible difference depending on age. This study demonstrates an increase in the expression of CYP3A29, the CYP3A4 orthologue in perinatal minipigs as in humans, which suggests that the minipig could be a good model when testing for human foetal toxicity towards CYP3A4 substrates.

scholarly journals Human Cytochrome P450 3A4 as a Biocatalyst: Effects of the Engineered Linker in Modulation of Coupling Efficiency in 3A4-BMR Chimeras

2017 ◽  
Vol 8 ◽  
Author(s):  
Danilo Degregorio ◽  
Serena D'Avino ◽  
Silvia Castrignanò ◽  
Giovanna Di Nardo ◽  
Sheila J. Sadeghi ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Coupling Efficiency ◽  
Cytochrome P450 3A4 ◽  
Human Cytochrome

Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity

2010 ◽  
Vol 48 (1) ◽  
pp. 429-435 ◽  
Author(s):  
Yuka Kimura ◽  
Hideyuki Ito ◽  
Ryoko Ohnishi ◽  
Tsutomu Hatano
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 3A4 ◽  
Inhibitory Effects ◽  
Human Cytochrome

Evaluation of the inhibition of chlorophenols towards human cytochrome P450 3A4 and differences among various species

2020 ◽  
Vol 724 ◽  
pp. 138187
Author(s):  
Nai-Rong Liu ◽  
Kai Yang ◽  
Wen-Ting Li ◽  
Zhi-Hua Pang ◽  
Qing Zhang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 3A4 ◽  
Human Cytochrome

Bioconversion of deoxypodophyllotoxin into epipodophyllotoxin in E. coli using human cytochrome P450 3A4

2006 ◽  
Vol 126 (3) ◽  
pp. 383-393 ◽  
Author(s):  
Nikolay P. Vasilev ◽  
Mattijs K. Julsing ◽  
Albert Koulman ◽  
Cailean Clarkson ◽  
Herman J. Woerdenbag ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 3A4 ◽  
E Coli ◽  
Human Cytochrome

Phosphorodiamidate Morpholino Antisense Oligomers Inhibit Expression of Human Cytochrome P450 3A4 and Alter Selected Drug Metabolism

2002 ◽  
Vol 30 (7) ◽  
pp. 757-762 ◽  
Author(s):  
Vikram Arora ◽  
Melissa L. Cate ◽  
Chandramallika Ghosh ◽  
Patrick L. Iversen
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Cytochrome P450 3A4 ◽  
Human Cytochrome
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