Comparison of the Substrate Specificities of Human Liver Cytochrome P450s 2C9 and 2C18:  Application to the Design of a Specific Substrate of CYP 2C18

Biochemistry ◽  
1999 ◽  
Vol 38 (24) ◽  
pp. 7828-7836 ◽  
Author(s):  
Claire Minoletti ◽  
Sylvie Dijols ◽  
Patrick M. Dansette ◽  
Daniel Mansuy
Keyword(s):  
Human Liver ◽  
Cytochrome P450s ◽  
Specific Substrate ◽  
Substrate Specificities ◽  
Liver Cytochrome

scholarly journals Identification of Human Liver Cytochrome P450s Involved in the Microsomal Metabolism of the Antihistaminic Drug Loratadine

1995 ◽  
Vol 107 (1-3) ◽  
pp. 420-420 ◽  
Author(s):  
Nathan Yumibe ◽  
Keith Huie ◽  
Kwang-Jong Chen ◽  
Robert P. Clement ◽  
Mitchell N. Cayen
Keyword(s):  
Human Liver ◽  
Cytochrome P450s ◽  
Microsomal Metabolism ◽  
Liver Cytochrome ◽  
Antihistaminic Drug

scholarly journals Determining the IC50 Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver

2015 ◽  
Vol 2015 ◽  
pp. 1-4 ◽  
Author(s):  
Lendelle Raymond ◽  
Nikita Rayani ◽  
Grace Polson ◽  
Kylie Sikorski ◽  
Ailin Lian ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
High Throughput Screening ◽  
Human Liver ◽  
Potent Inhibitor ◽  
Cytochrome P450s ◽  
Third Generation ◽  
Weak Inhibitor ◽  
Liver Cytochrome ◽  
Ic50 Values ◽  
Screening Assays

Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [11C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liver. In search of finding the protein responsible for the accumulation of vorozole in the liver, fluorometric high-throughput screening assays were used to test the inhibitory capability of vorozole and letrozole on a series of liver cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, and CYP3A4). It was determined that vorozole is a potent inhibitor of CYP1A1 (IC50 = 0.469 μM) and a moderate inhibitor of CYP2A6 and CYP3A4 (IC50 = 24.4 and 98.1 μM, resp.). Letrozole is only a moderate inhibitor of CYP1A1 and CYP2A6 (IC50 = 69.8 and 106 μM) and a very weak inhibitor of CYP3A4 (<10% inhibition at 1 mM). Since CYP3A4 makes up the majority of the CYP content found in the human liver, and vorozole inhibits it moderately well but letrozole does not, CYP3A4 is a good candidate for the protein that [11C]-vorozole is binding to in the liver.

scholarly journals Hydroxylation of antitubercular drug candidate, SQ109, by mycobacterial cytochrome P450

2020 ◽  
Author(s):  
Sergey Bukhdruker ◽  
Tatsiana Varaksa ◽  
Irina Grabovec ◽  
Egor Marin ◽  
Polina Shabunya ◽  
...  
Keyword(s):  
Human Liver ◽  
Multidrug Resistant ◽  
Cytochrome P450s ◽  
Drug Candidate ◽  
Antitubercular Drug ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Methyl Group ◽  
Liver Cytochrome ◽  
Effective Drugs

AbstractSpreading of the multidrug-resistant (MDR) strains of the deadliest pathogen Mycobacterium tuberculosis (Mtb) generates the need for new effective drugs. SQ109 showed activity against resistant Mtb and already advanced to Phase II/III clinical trials. Fast SQ109 degradation is attributed to the human liver Cytochrome P450s (CYPs). However, no information is available about interactions of the drug with Mtb CYPs. Here, we show that Mtb CYP124, previously assigned as a methyl-branched lipid monooxygenase, binds and hydroxylates SQ109 in vitro. A 1.25 Å-resolution crystal structure of the CYP124–SQ109 complex unambiguously shows two conformations of the drug, both positioned for hydroxylation of the ω-methyl group in the trans position. The hydroxylated SQ109 presumably forms stabilizing H-bonds with its target, the Mycobacterial membrane protein Large 3 (MmpL3). We anticipate that Mtb CYPs could function as analogs of drug-metabolizing human CYPs affecting pharmacokinetics and pharmacodynamics of antitubercular (anti-TB) drugs.

Identification of Human Liver Cytochrome P450 Enzymes Involved in Biotransformation of Vicriviroc, a CCR5 Receptor Antagonist

2007 ◽  
Vol 35 (12) ◽  
pp. 2186-2195 ◽  
Author(s):  
Anima Ghosal ◽  
Ragu Ramanathan ◽  
Yuan Yuan ◽  
Neil Hapangama ◽  
Swapan K. Chowdhury ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Receptor Antagonist ◽  
Human Liver ◽  
Cytochrome P450 Enzymes ◽  
Liver Cytochrome ◽  
Ccr5 Receptor

scholarly journals Toward a systems approach to cytochrome P450 ensemble: interactions of CYP2E1 with other P450 species and their impact on CYP1A2

2019 ◽  
Vol 476 (23) ◽  
pp. 3661-3685 ◽  
Author(s):  
Nadezhda Y. Davydova ◽  
Bikash Dangi ◽  
Marc A. Maldonado ◽  
Nikita E. Vavilov ◽  
Victor G. Zgoda ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Systems Approach ◽  
Liver Microsomes ◽  
Model System ◽  
Human Liver Microsomes ◽  
Microsomal Membrane ◽  
Specific Substrate ◽  
Main Route ◽  
Functional Differences

In this study, we investigate the ability of ethanol-inducible CYP2E1 to interact with other cytochrome P450 species and affect the metabolism of their substrates. As a model system, we used CYP2E1-enriched human liver microsomes (HLM) obtained by the incorporation of purified CYP2E1. Using a technique based on homo-FRET in oligomers of CYP2E1 labeled with BODIPY 577/618 maleimide we demonstrated that the interactions of CYP2E1 with HLM result in the formation of its mixed oligomers with other P450 species present in the microsomal membrane. Incorporation of CYP2E1 results in a multifold increase in the rate of metabolism of CYP2E1-specific substrates p-Nitrophenol and Chlorzaxozone. The rate of their oxidation remains proportional to the amount of incorporated CYP2E1 up to the content of 0.3–0.4 nmol/mg protein (or ∼50% CYP2E1 in the P450 pool). The incorporated CYP2E1 becomes a fully functional member of the P450 ensemble and do not exhibit any detectable functional differences with the endogenous CYP2E1. Enrichment of HLM with CYP2E1 results in pronounced changes in the metabolism of 7-ethoxy-4-cyanocoumarin (CEC), the substrate of CYP2C19 and CYP1A2 suggesting an increase in the involvement of the latter in its metabolism. This effect goes together with an augmentation of the rate of dealkylation of CYP1A2-specific substrate 7-ethoxyresorufin. Furthermore, probing the interactions of CYP2E1 with model microsomes containing individual P450 enzymes we found that CYP2E1 efficiently interacts with CYP1A2, but lacks any ability to form complexes with CYP2C19. This finding goes inline with CYP2E1-induced redirection of the main route of CEC metabolism from CYP2C19 to CYP1A2.

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