Mechanism-Based Inhibition of Human Liver Microsomal Cytochrome P450 2D6 (CYP2D6) by Alkamides of Piper nigrum

Abstract

Nineteen alkamides isolated from Piper nigrum L. were tested for their mechanism-based inhibition on human liver microsomal dextromethorphan O-demethylation activity, a prototype marker for cytochrome P450 2D6 (CYP2D6). All compounds increased their inhibitory activity with increasing preincubation time. Among them, 15 and 17 showed more than 50 % decrease of the CYP2D6 residual activity after 20 min preincubation. Further investigations on 15 and 17 showed that the characteristic time- and concentration-dependent inhibition, which required a catalytic step with NADPH, was not protected by nucleophiles, and was decreased by the presence of a competitive inhibitor. The kinetic parameters for inactivation (k _inact and K _I) were 0.028 min^-1 and 0.23 μM for 15 and 0.064 min^-1 and 0.71 μM for 17, respectively, which were stronger than the known mechanism-based inhibitor, paroxetine (a positive control). Thus, 15 and 17 are potent mechanism-based inhibitors of CYP2D6.

Piper nigrum - alkamides - cytochrome P450 2D6 - CYP2D6 - mechanism-based inhibition - drug-herb interaction

References

• 1 Thayer W S. Biotransformation. In: DiPalma JR, DiGregorio GJ, editors Basic pharmacology in medicine. 3rd Edition New York; McGraw-Hill Publishing Company 1989: p 52-62
• 2 Guengerich F P. In vitro techniques for studying drug metabolism.  J Pharmacokinet Biopharm. 1996;  24 521-33
• 3 Clarke S E, Jones B C. Human cytochromes P450 and their role in metabolism-based drug-drug interactions. In: Rodrigues AD, editor Drug-drug interactions. New York; Marcel Dekker 2002: p 55-8
• 4 Lin J H, Lu A YH. Inhibition and induction of cytochrome P450 and the clinical implications.  Clin Pharmacokinet. 1998;  35 361-90
• 5 Silverman R B. Mechanism-based enzyme inactivation: chemistry and enzymology I. Florida; CRC Press 1988: p 1-30
• 6 Chun Y J, Ryu S Y, Jeong T C, Kim M Y. Mechanism-based inhibition of human cytochrome P450 1A1 by rhapontigenin.  Drug Metab Dispos. 2001;  29 389-93
• 7 Tassaneeyakul W, Guo L Q, Fukuda K, Ohta T, Yamazoe Y. Inhibition selectivity of grapefruit juice components on human cytochrome P450 3A4.  Arch Biochem Biophys. 2000;  376 356-63
• 8 Chan W K, Delucchi A B. Resveratrol, a red wine constituent, is a mechanism-based inactivator of cytochrome P450 3A4.  Life Sci. 2000;  67 3102-12
• 9 Chan T KH, Chen J, Lee W BK. Differential inhibition and inactivation of human CYP1 enzymes by trans-resveratrol: evidence for mechanism-based inactivation of CYP1A2.  J Pharmacol Exp Ther. 2001;  299 874-82
• 10 Usia T, Watabe T, Kadota S, Tezuka Y. Metabolite-cytochrome P450 complex formation by methylenedioxyphenyl lignans of Piper cubeba: mechanism-based inhibition.  Life Sci. 2005;  76 2381-91
• 11 Usia T, Watabe T, Kadota S, Tezuka Y. Mechanism-based inhibition of CYP3A4 by constituents of Zingiber aromaticum .  Biol Pharm Bull. 2005;  28 495-9
• 12 Usia T, Watabe T, Kadota S, Tezuka Y. Cytochrome P450 2D6 (CYP2D6) inhibitory constituents of Catharanthus roseus .  Biol Pharm Bull. 2005;  28 1021-4
• 13 Jo B. Medicinal herb index in Indonesia. Jakarta; PT Eisai Indonesia 1995: p 275
• 14 Tsukamoto S, Cha B C, Ohta T. Dipiperamides A, B, and C: bisalkaloids from the white pepper Piper nigrum inhibiting CYP3A4 activity.  Tetrahedron. 2002;  58 1667-71
• 15 Tsukamoto S, Tomise K, Miyakawa K, Cha B C, Abe T, Hamada T. et al . CYP3A4 inhibitory activity of new bisalkaloids, dipiperamides D and E, and cognates from white pepper.  Bioorg Med Chem. 2002;  10 2981-5
• 16 Koul S, Koul J L, Taneja S C, Dhar K L, Jamwal D S, Singh K. et al . Structure-activity relationship of piperine and its synthetic analogues for their inhibitory potentials of rat hepatic microsomal constitutive and inducible cytochrome P450 activities.  Bioorg Med Chem. 2000;  8 251-68
• 17 Iwata H, Tezuka Y, Kadota S, Hiratsuka A, Watabe T. Metabolism-dependent inhibition of CYP3A4 and CYP2D6 by extracts from 26 herbal medicines.  J Tradit Med. 2004;  21 281-6
• 18 Rodrigues A D. Measurement of human liver microsomal cytochrome P450 2D6 activity using [O-methyl-14C]dextromethorphan as substrate. In: Johnson EF, Waterman MR, editors Cytochrome P450. New York; Academic Press 1996: p 86-195
• 19 Deans S G. Book reviews: black pepper, Piper nigrum. Medicinal and aromatic plants-industrial profiles.  Phytochemistry. 2001;  58 827-9
• 20 Bhardwaj R K, Glaeser H, Becquemont L, Klotz U, Gupta S K, Fomm M F. Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4.  J Pharmacol Exp Ther. 2002;  302 645-50
• 21 Yuan R, Madani S, Wei X, Reynolds K, Huang S. Evaluation of cytochrome P450 probe substrates commonly used by the pharmaceutical industry to study in vitro drug interactions.  Drug Metab Dispos. 2002;  30 1311-9
• 22 Bertelsen K M, Venkatakrishnan K, Moltke L LV, Obach R S, Greenblatt D J. Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine.  Drug Metab Dispos. 2003;  31 289-93
• 23 Guengerich F P, Muller E D, Blair I A. Oxidation of quinidine by human liver cytochrome P-450.  Mol Pharmacol. 1986;  30 287-95
• 24 Nelson S D. Metabolic activation and drug toxicity.  J Med Chem. 1982;  25 753-65
• 25 Moruno-Davila M A, Garrido-deSolo C, Garcia-Moreno M, Havsteen B H, Garcia-Sevilla F, Garcia-Canovas F. et al . Kinetic analysis of enzyme systems with suicides substrate in the presence of a reversible competitive inhibitor, tested by simulated progress curves.  Int J Biochem Cell Biol. 2001;  33 181-91
• 26 Walsh C. Suicide substrates: mechanism-based enzyme inactivators.  Tetrahedron. 1982;  38 871-909
• 27 Murray M. Mechanism of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation.  Curr Drug Metab. 2000;  1 67-84