Biotransformation of 8:2 fluorotelomer alcohol by recombinant human cytochrome P450s, human liver microsomes and human liver cytosol

Osthenol is a prenylated coumarin isolated from the root of Angelica koreana and Angelica dahurica, and is an O-demethylated metabolite of osthole in vivo. Its various pharmacological effects have been reported previously. The metabolic pathway of osthenol was partially confirmed in rat osthole studies, and 11 metabolic products were identified in rat urine. However, the metabolic pathway of osthenol in human liver microsomes (HLM) has not been reported. In this study, we elucidated the structure of generated metabolites using a high-resolution quadrupole-orbitrap mass spectrometer (HR-MS/MS) and characterized the major human cytochrome P450 (CYP) and uridine 5′-diphospho-glucuronosyltransferase (UGT) isozymes involved in osthenol metabolism in human liver microsomes (HLMs). We identified seven metabolites (M1-M7) in HLMs after incubation in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and uridine 5′-diphosphoglucuronic acid (UDPGA). As a result, we demonstrated that osthenol is metabolized to five mono-hydroxyl metabolites (M1-M5) by CYP2D6, 1A2, and 3A4, respectively, a 7-O-glucuronide conjugate (M6) by UGT1A9, and a hydroxyl-glucuronide (M7) from M5 by UGT1A3 in HLMs. We also found that glucuronidation is the dominant metabolic pathway of osthenol in HLMs.

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Oxidation of 2,6-Dimethylaniline by Recombinant Human Cytochrome P450s and Human Liver Microsomes

Chemical Research in Toxicology ◽

10.1021/tx000181i ◽

2001 ◽

Vol 14 (6) ◽

pp. 672-677 ◽

Cited By ~ 20

Author(s):

Jinping Gan ◽

Paul L. Skipper ◽

Steven R. Tannenbaum

Keyword(s):

Human Liver ◽

Liver Microsomes ◽

Cytochrome P450s ◽

Human Liver Microsomes ◽

Human Cytochrome

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Detoxification of the tricyclic antidepressant opipramol and its analog – IS-noh by UGT enzymes before and after activation by phase I enzymes in rat liver microsomes

Chemical Papers ◽

10.1007/s11696-021-01647-2 ◽

2021 ◽

Author(s):

Anna Mieszkowska ◽

Koleta Hemine ◽

Anna Skwierawska ◽

Ewa Augustin ◽

Zofia Mazerska

Keyword(s):

Phase I ◽

Rat Liver ◽

Phase Ii ◽

Oxidation Product ◽

Liver Microsomes ◽

Correct Selection ◽

Rat Liver Microsomes ◽

Recombinant Enzymes ◽

Data Set ◽

Phase I Enzymes

AbstractThe present studies were carried out to evaluate the simultaneous one-pot metabolism of opipramol (IS-opi) and analog (IS-noh) by phase I and phase II enzymes present in rat liver microsomes (RLM) as an alternative to separate testing with recombinant enzymes. This approach allows for more time-saving and cost-effective screening of the metabolism of newly discovered drugs. We also considered that the lack of results for phase II, including UGT, often creates problems in correct selection of valuable compounds. Moreover, microsomes data set is richer in the contest and provides medical scientist to determine also the susceptibility of drugs to undergo phase I and then phase II. In the present work, we have shown that IS-noh was metabolized in vitro by phase I enzymes to the oxidation product, which was next transformed with UGTs to glucuronide. The results showed also that the previously known oxidation product of opipramol was changed to previously no reported glucuronidation product by UDP-glucuronosyltransferases. In addition, unlike IS-noh, opipramol did not prove to be the substrate for UGTs. Therefore, tricyclic antidepressants depending on the structure can trigger a different response after contact with UGT enzymes. Some will metabolize directly with UGTs, others only after activation by phase I enzymes.

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