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In vitro metabolism of nobiletin, a polymethoxy-flavonoid, by human liver microsomes and cytochrome P450.
Xenobiotica. 2011 Nov; 41(11):927-33.X

Abstract

Cytochrome P450 enzymes (CYPs) in the liver metabolize drugs prior to excretion, with different enzymes acting at different molecular motifs. At present, the human CYPs responsible for the metabolism of the flavonoid, nobiletin (NBL), are unidentified. We investigated which enzymes were involved using human liver microsomes and 12 cDNA-expressed human CYPs. Human liver microsomes metabolized NBL to three mono-demethylated metabolites (4'-OH-, 7-OH- and 6-OH-NBL) with a relative ratio of 1:4.1:0.5, respectively, by aerobic incubation with nicotinamide adenine dinucleotide phosphate (NADPH). Of 12 human CYPs, CYP1A1, CYP1A2 and CYP1B1 showed high activity for the formation of 4'-OH-NBL. CYP3A4 catalyzed the formation of 7-OH-NBL with the highest activity and of 6-OH-NBL with lower activity. CYP3A5 also catalyzed the formation of both metabolites but considerably more slowly than CYP3A4. In contrast, seven CYPs (CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1) were inactive for NBL. Both ketoconazole and troleandomycin (CYP3A inhibitors) almost completely inhibited the formation of 7-OH- and 6-OH-NBL. Similarly, α-naphthoflavone (CYP1A1 inhibitor) and furafylline (CYP1A2 inhibitor) significantly decreased the formation of 4'-OH-NBL. These results suggest that CYP1A2 and CYP3A4 are the key enzymes in human liver mediating the oxidative demethylation of NBL in the B-ring and A-ring, respectively.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Koga N
Faculty of Nutritional Sciences, Nakamura Gakuen University, Johnan-ku, Fukuoka, Japan. nobuyuki@nakamura-u.ac.jp
Ohta C
No affiliation info available
Kato Y
No affiliation info available
Haraguchi K
No affiliation info available
Endo T
No affiliation info available
Ogawa K
No affiliation info available
Ohta H
No affiliation info available
Yano M
No affiliation info available

MeSH

AnimalsChromatography, High Pressure LiquidCricetinaeCytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemEnzyme InhibitorsFemaleFlavonesGuinea PigsHumansMaleMicrosomes, LiverRatsRats, WistarRecombinant Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21726170

Citation

Koga, Nobuyuki, et al. "In Vitro Metabolism of Nobiletin, a Polymethoxy-flavonoid, By Human Liver Microsomes and Cytochrome P450." Xenobiotica; the Fate of Foreign Compounds in Biological Systems, vol. 41, no. 11, 2011, pp. 927-33.
Koga N, Ohta C, Kato Y, et al. In vitro metabolism of nobiletin, a polymethoxy-flavonoid, by human liver microsomes and cytochrome P450. Xenobiotica. 2011;41(11):927-33.
Koga, N., Ohta, C., Kato, Y., Haraguchi, K., Endo, T., Ogawa, K., Ohta, H., & Yano, M. (2011). In vitro metabolism of nobiletin, a polymethoxy-flavonoid, by human liver microsomes and cytochrome P450. Xenobiotica; the Fate of Foreign Compounds in Biological Systems, 41(11), 927-33. https://doi.org/10.3109/00498254.2011.593208
Koga N, et al. In Vitro Metabolism of Nobiletin, a Polymethoxy-flavonoid, By Human Liver Microsomes and Cytochrome P450. Xenobiotica. 2011;41(11):927-33. PubMed PMID: 21726170.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro metabolism of nobiletin, a polymethoxy-flavonoid, by human liver microsomes and cytochrome P450. AU - Koga,Nobuyuki, AU - Ohta,Chiho, AU - Kato,Yoshihisa, AU - Haraguchi,Koichi, AU - Endo,Tetsuya, AU - Ogawa,Kazunori, AU - Ohta,Hideaki, AU - Yano,Masamichi, Y1 - 2011/07/05/ PY - 2011/7/6/entrez PY - 2011/7/6/pubmed PY - 2012/2/11/medline SP - 927 EP - 33 JF - Xenobiotica; the fate of foreign compounds in biological systems JO - Xenobiotica VL - 41 IS - 11 N2 - Cytochrome P450 enzymes (CYPs) in the liver metabolize drugs prior to excretion, with different enzymes acting at different molecular motifs. At present, the human CYPs responsible for the metabolism of the flavonoid, nobiletin (NBL), are unidentified. We investigated which enzymes were involved using human liver microsomes and 12 cDNA-expressed human CYPs. Human liver microsomes metabolized NBL to three mono-demethylated metabolites (4'-OH-, 7-OH- and 6-OH-NBL) with a relative ratio of 1:4.1:0.5, respectively, by aerobic incubation with nicotinamide adenine dinucleotide phosphate (NADPH). Of 12 human CYPs, CYP1A1, CYP1A2 and CYP1B1 showed high activity for the formation of 4'-OH-NBL. CYP3A4 catalyzed the formation of 7-OH-NBL with the highest activity and of 6-OH-NBL with lower activity. CYP3A5 also catalyzed the formation of both metabolites but considerably more slowly than CYP3A4. In contrast, seven CYPs (CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1) were inactive for NBL. Both ketoconazole and troleandomycin (CYP3A inhibitors) almost completely inhibited the formation of 7-OH- and 6-OH-NBL. Similarly, α-naphthoflavone (CYP1A1 inhibitor) and furafylline (CYP1A2 inhibitor) significantly decreased the formation of 4'-OH-NBL. These results suggest that CYP1A2 and CYP3A4 are the key enzymes in human liver mediating the oxidative demethylation of NBL in the B-ring and A-ring, respectively. SN - 1366-5928 UR - https://www.unboundmedicine.com/medline/citation/21726170/In_vitro_metabolism_of_nobiletin_a_polymethoxy_flavonoid_by_human_liver_microsomes_and_cytochrome_P450_ DB - PRIME DP - Unbound Medicine ER -