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Inhibition of human drug metabolizing cytochrome P450 enzymes by plant isoquinoline alkaloids.

Summary of "Inhibition of human drug metabolizing cytochrome P450 enzymes by plant isoquinoline alkaloids."

The human cytochrome P450 (CYP) enzymes play a major role in the metabolism of endobiotics and numerous xenobiotics including drugs. Therefore it is the standard procedure to test new drug candidates for interactions with CYP enzymes during the preclinical development phase. The purpose of this study was to determine in vitro CYP inhibition potencies of a set of isoquinoline alkaloids to gain insight into interactions of novel chemical structures with CYP enzymes. These alkaloids (n=36) consist of compounds isolated from the Papaveraceae family (n=20), synthetic analogs (n=15), and one commercial compound. Their inhibitory activity was determined towards all principal human drug metabolizing CYP enzymes: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4. All alkaloids were assayed in vitro in a 96-well plate format using pro-fluorescent probe substrates and recombinant human CYP enzymes. Many of these alkaloids inhibited the CYP3A4 form, with 30/36 alkaloids inhibiting CYP3A4 with at least moderate potency (IC(50)<10μM) and 15/36 inhibiting CYP3A4 potently (IC(50)<1μM). Among them corydine, parfumine and 8-methyl-2,3,10,11-tetraethoxyberbine were potent and selective inhibitors for CYP3A4. CYP2D6 was inhibited with at least moderate potency by 26/34 alkaloids. CYP2C19 was inhibited by 15/36 alkaloids at least moderate potently, whereas CYP1A2, CYP2B6, CYP2C8, and CYP2C9 were inhibited to a lesser degree. CYP2A6 was not significantly inhibited by any of the alkaloids. The results provide initial structure-activity information about the interaction of isoquinoline alkaloids with major human xenobiotic-metabolizing CYP enzymes, and illustrate potential novel structures as CYP form-selective inhibitors.

Affiliation

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.

Journal Details

This article was published in the following journal.

Name: Phytomedicine : international journal of phytotherapy and phytopharmacology
ISSN: 1618-095X
Pages:

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Medical and Biotech [MESH] Definitions

A cytochrome P450 enzyme family that includes members with critical functions in the metabolism of drugs and SEX HORMONES.

A cytochrome P450 enzyme family whose members localize to the INNER MITOCHONDRIAL MEMBRANE where they function in the biosynthesis of STEROIDS.

A cytochrome P450 enzyme family that functions in the biosynthesis of STEROIDS and includes STEROID 17-ALPHA-HYDROXYLASE.

A cytochrome P450 enzyme family whose members function in VITAMIN D metabolism and the biosynthesis of BILE ACIDS.

A cytochrome P450 enzyme family that includes members which function in the metabolism of STEROIDS; COUMARINS; and NICOTINE.

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