Drug–herb interaction through inhibition of cytochrome P450 alters the pharmacological response and/or toxicities of drug used concomitantly. In our screening, Piper nigrum L. was observed to inhibit cytochrome P450 2D6 (CYP2D6) in human liver microsomes. Thus, the MeOH extract of this plant was investigated for their chemical constituents and 19 alkamides including a new pipercyclobutanamide were isolated. Their structures were elucidated on the basis of spectroscopic analyses. The isolated compounds were tested for their inhibition on human liver microsomal dextromethorphan O-demethylation activity, a selective marker for CYP2D6, and pipercyclobutanamide A (17) showed the most potent inhibition with an IC50 value of 0.34 μM. The result demonstrated the potential of drug–alkamides interaction on concomitant consume of white pepper with the drugs being metabolized by CYP2D6.
ThayerWS. (1989) Biotransformation. In Basic Pharmacology in Medicine, 3rd Edition. DiPalmaJR, DiGregorioGJ (Eds). McGraw-Hill, New York, 52–62.
2.
GoodmanLS, GilmanA. (1995) Goodman and Gilman's The Pharmacological Basis of Therapeutics. MalinoffPB., RuddonRW (Eds). McGraw-Hill, New York. 11–16.
3.
LinJH, LuAYH. (1998) Inhibition and induction of cytochrome P450 and the clinical implications. Clinical Pharmacokinetics, 35, 361–390.
4.
HeydariA, YeoKR, LennardMS, EllisSW, TuckerGT, Rostami-HodjeganA. (2004) Mechanism-based Inactivation of CYP2D6 by methylenedioxymethamphetamine. Drug Metabolism and Disposition, 32, 1213–1217.
5.
MadanA, UsukiE, BurtonLA, OgilvieBW, ParkinsonA, (2002). In vitro approaches for studying the inhibition of drug-metabolizing enzymes and identifying the drug-metabolizing enzymes responsible for the metabolism of drugs. In Drug-drug Interactions. RodriguesAD. (Ed). Marcel Dekker, New York, 217–293.
6.
BudzinskiJW, FosterBC, VandenhoekS, ArnasonJT. (2000) An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Phytomedicine, 7, 273–282.
7.
ZhouS, KohHL, GaoY, GongZ, LeeEJD. (2004) Herbal bioactivation: The good, the bad and the ugly. Life Sciences, 74, 935–968.
8.
HeK, IyerKR, HeyesRN, SinzMW, WoolfTF, HollenbergPH. (2000) Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit juice. Chemical Research in Toxicology, 11, 252–259.
9.
SurhYJ, LeSS. (1995) Capsaicin, a double edged sword: toxicity, metabolism, and chemopreventive potential. Life Sciences, 56, 1845–1855.
10.
BradyJF, IshizakiH, FukotoJM, LinMC, FadelA, GapacJM, YangCS. (1991) Inhibition of cytochrome P-450 2E1 by diallyllsulfide and its metabolites. Chemical Research in Toxicology, 4, 642–647.
11.
UsiaT, IwataH, HiratsukaA, WatabeT, KadotaS, TezukaY. (2004) Sesquiterpenes and flavonol glycosides from Zingiber aromaticum and their CYP3A4 and CYP2D6 inhibitory activities. Journal of Natural Products, 67, 1079–1083.
12.
UsiaT, WatabeT, KadotaS, TezukaY. (2005) Potent CYP3A4 inhibitory constituents of Piper cubeba. Journal of Natural Products, 68, 64–68.
13.
UsiaT, WatabeT, KadotaS, TezukaY. (2005) Cytochrome P450 2D6 (CYP2D6) inhibitory constituents of Catharanthus roseus. Biological and Pharmaceutical Bulletin, 28, 1021–1024.
14.
UsiaT, IwataH, HiratsukaA, WatabeT, KadotaS, TezukaY. (2005) CYP3A4 and CYP2D6 inhibitory activities of Indonesian medicinal plants. Phytomedicine, 13, 67–73.
15.
DeansSG. (2001) Book Reviews: Black pepper, Piper nigrum. Medicinal and aromatic plants–industrial profiles. Phytochemistry, 58, 827–829.
16.
Medicinal Herb Index in Indonesia, PT Eisai Indonesia, Jakarta, 1995. p 275.
17.
WeiK, LiW, KoikeK, ChenY, NikaidoT. (2005) Nigramid A-S, dimeric amide alkaloids from the roots of Piper nigrum. Journal of Organic Chemistry, 70, 1164–1176.
18.
TsukamotoS, ChaBC, OhtaT. (2002) Dipiperamide A, B, and C: bisalkaloids from the white pepper Piper nigrum inhibiting CYP3A4. Tetrahedron, 58, 1667–1671.
19.
TsukamotoS, TomiseK, MiyakawaK, ChaBC, AbeT, HamadaT, HirotaH, OhtaT. (2002) CYP3A4 inhibitory activity of new bisalkaloids, dipiperamides D and E, and cognates from white pepper. Bioorganic Medicinal Chemistry, 10, 2981–2985.
20.
KoulS, KoulJL, TanejaSC, DharKL, JamwalDS, SinghK, ReenRK, SinghJ. (2000) Structure–activity relationship of piperine and its synthetic analogues for their inhibitory potentials of rat hepatic microsomal constitutive and inducible cytochrome P450 activities. Bioorganic Medicinal Chemistry, 8, 251–268.
21.
SimTB, YoonNM. (1994) Convenient direct synthesis of amides from carboxylic acid esters using sodium diethyldiamidoaluminate. Synlett, 10, 827–828.
22.
RosarioSL, da SilvaAJR, ParenteJP. (1996) Alkamides from Cissampelos glaberrima. Planta Medica, 62, 376–377.
NakataniN, InataniR, OhtaH, NishiokaA. (1986) Chemical constituents of peppers (Piper spp.) and application to food preservation: Naturally occurring antioxidative compounds. Environmental Health Perspectives, 67, 135–142.
KollmannsbergerH, NitsS. (1992) Amides from supercritical fluid extracts of muntok pepper. Chemie Mikrobiologie Technologie der Lebensmittel, 14, 87–91.
27.
Addae-MensahI, TortoFG, OppongIV, BaxterI, SandersJKM. (1977) N-isobutyl-trans-2-trans-4-eicosadienamide and other alkaloids of fruits of Piper guineense. Phytochemistry, 16, 483–485.
28.
KiuchiF, NakamuraN, TsudaY, KondoK, YoshimuraH. (1988) Studies on crude drugs effective on visceral larva migrans. IV. Isolation and identification of larvicidal principles in pepper. Chemical and Pharmaceutical Bulletin, 36, 2452–2465.
29.
ShojiN, UmeyamaA, SaitoN, TakemotoT, KajiwaraA, OhizumiY. (1987) Dehydropipernonaline, an amide possessing coronary vasodilating activity, isolated from Piper longum L. Journal of Pharmaceutical Science, 75, 1188–1189.
30.
DasB, KashinathamA, MadhusudhanP. (1998) Regioselective reduction of the α,β-double bond of some naturally occurring dienamides using NaBH4/I2 system. Tetrahedron Letters, 39, 677–678.
FujiwaraY, NaithouK, MiyazakiT, HashimotoK, MoriK, YamamotoY. (2001) Two new alkaloids, pipercyclobutanamides A and B, from Piper nigrum. Tetrahedron letter, 42, 2497–2499.
33.
gNMR program V4.1.0. Cherwill scientific publishing.
34.
CibinFR, DoddiG, MencarelliP. (2003) Photocycloaddition of chalcones to yield cyclobutyl ditopic cyclophanes. Tetrahedron, 59, 9971–9978.
35.
TakahashiM, IchikawaM, AoyagiS, KibayashiC. (2005) Total synthesis of dipiperamide A and revision of stereochemical assignment. Tetrahedron Letters, 46, 57–59.
36.
FilhoRB, De SouzaMP, MattosMEO. (1981) Piplartine-dimer A, A new alkaloid from Piper tuberculatum. Phytochemistry, 20, 345–346.
37.
MurrayM. (2000) Mechanism of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation. Current Drug Metabolism, 1, 67–84.
38.
RodriguesFP. (1996) Measurement of human liver microsomal cytochrome P450 2D6 activity using [O-Methyl-14C]-dextromethorphan as substrate. In Cytochrome P450. JohnsonEF, WatermanMR. (Eds). Academic Press, New York, 186–195.
