Archives of Pharmacal Research

  • 제27권2호
  • /
  • Pages.199-205
  • /
  • 2004
  • /
  • 0253-6269(pISSN)
  • /
  • 1976-3786(eISSN)
대한약학회 (The Pharmaceutical Society of Korea)
권호 표지

Potent Inhibition of Human Cytochrome P450 1 Enzymes by Dimethoxyphenylvinyl Thiophene

  • Lee, Sang-Kwang (College of Pharmacy, Chung-Ang University) ;
  • Kim, Yongmo (College of Pharmacy, Chung-Ang University) ;
  • Kim, Mie-Young (College of Pharmacy, Chung-Ang University) ;
  • Kim, Sanghee (Natural Products Research Institute, College of Pharmacy, Seoul National University) ;
  • Chun, Young-Jin (College of Pharmacy, Chung-Ang University)
  • 발행 : 2004.02.01
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Cytochrome P450 (P450) 1 enzymes such as P450 1A1, 1A2, and 181 are known to be involved in the oxidative metabolism of various procarcinogens and are regarded as important target enzymes for cancer chemoprevention. Previously, several hydroxystilbene compounds were reported to inhibit P450 1 enzymes and were rated as candidate chemopreventive agents. In this study, we investigated the inhibitory effect of 2-[2-(3,5-dimethoxyphenyl)vinyl]-thiophene (DMPVT), produced from the chemical modification of oxyresveratrol, on the activities of P450 1 enzymes. The inhibitory potential by DMPVT on the P450 1 enzyme activity was evaluated with the Escherichia coli membranes of the recombinant human cytochrome P450 1A1, 1A2, or 1B1 coexpressed with human NADPH-P450 reductase. DMPVT significantly inhibited ethoxyresorufin O-deethylation (EROD) activities with $IC_{50}$ values of 61, 11, and 2 nM for 1A1, 1A2, and 1B1, respectively. The EROO activity in OMBA-treated rat lung microsomes was also significantly inhibited by OMPVT in a dose-dependent manner. The modes of inhibition by DMPVT were non-competitive for all three P450 enzymes. The inhibition of P450 1B1-mediated EROD activity by OMPVT did not show the irreversible mechanism-based effect. The loss of EROD activity in P450 1B1 with OMPVT incubation was not blocked by treatment with the trapping agents such as glutathione, N-acetylcysteine, or dithiothreitol. Taken together, the results suggested DMPVT to be a strong noncompetitive inhibitor of human P450 1 enzymes that should be considered as a good candidate for a cancer chemopreventive agent in humans.

키워드

참고문헌

  1. Burke, M. D., Thompson, S., Elcombe, C. R., Halpert, J., Haaparanta, T., and Mayer, R. T., Ethoxy-, pentoxy- and benzyl-oxyphenoxazones and homologues: a series of substrates to distinguish between different induced cytochromes P-450. Biochem. Pharmacol., 34, 3337-3345 (1985) https://doi.org/10.1016/0006-2952(85)90355-7
  2. Cai, Y., Baer-Dubowska, W., Ashwood-Smith, M. J., Ceska, O., Tachibana, S., and DiGiovanni, J., Mechanism-based inactiva-tion of hepatic ethoxyresorufin O-dealkylation activity by naturally occurring coumarins. Chem. Res. Toxicol., 9, 729-736 (1996) https://doi.org/10.1021/tx950208b
  3. Chang, T. K., Lee, W. B., and Ko, H. H., Trans-resveratrol modulates the catalytic activity and mRNA expression of the procarcinogen-activating human cytochrome P450 1B1. Can. J. Physiol. Pharmacol., 78, 874-881 (2000) https://doi.org/10.1139/cjpp-78-11-874
  4. Cheong, H., Ryu, S. Y., and Kim, K. M., Anti-allergic action of resveratrol and related hydroxystilbenes. Planta Med., 65, 266-268 (1999) https://doi.org/10.1055/s-2006-960773
  5. Chun, Y. J., Kim, M. Y., and Guengerich, F. P., Resveratrol is a selective human cytochrome P450 1A1 inhibitor. Biochem. Biophys. Res. Commun., 262, 20-24 (1999) https://doi.org/10.1006/bbrc.1999.1152
  6. Chun, Y. J., Kim, S., Kim, D., Lee, S. K., and Guengerich, F. P., A new selective and potent inhibitor of human cytochrome P450 1B1 and its application to antimutagenesis. Cancer Res., 61, 8164-8170 (2001a)
  7. Chun, Y. J., Ryu, S. Y., Jeong, T. C., and Kim, M. Y., Mechanismbased inhibition of human cytochrome P450 1A1 by rhapontigenin. Drug Metab. Dispos., 29, 389-393 (2001b)
  8. Ciolino, H. P., Wang, T. T., and Yeh, G. C., Diosmin and diosmetin are agonists of the aryl hydrocarbon receptor that differentially affect cytochrome P450 1A1 activity. Cancer Res., 58, 2754-2760 (1998)
  9. Ciolino, H. P. and Yeh, G. C., The flavonoid galangin is an inhibitor of CYP1A1 activity and an agonist/antagonist of the aryl hydrocarbon receptor. Br. J. Cancer, 79, 1340-1346 (1999) https://doi.org/10.1038/sj.bjc.6690216
  10. Dawling, S., Roodi, N., and Parl, F. F., Methoxyestrogens exert feedback inhibition on cytochrome P450 1A1 and 1B1, Cancer Res., 63, 3127-3132 (2003)
  11. Doostdar, H., Burke, M. D., and Mayer, R. T., Bioflavonoids: selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1. Toxicology, 144, 31-38 (2000) https://doi.org/10.1016/S0300-483X(99)00215-2
  12. Fremont, L., Biological effects of resveratrol. Life Sci., 66, 663-673 (2000) https://doi.org/10.1016/S0024-3205(99)00410-5
  13. Guengerich, F. P., Analysis and characterization of enzymes, In Hayes, A.W. (Ed). Principles and Methods of Toxicology. Raven Press, New York, pp. 1259-1313, (1994)
  14. Guengerich, F. P., Martin, M. V., Guo, Z., and Chun, Y. J., Purification of functional recombinant P450s from bacteria. Methods Enzymol., 272, 35-44 (1996) https://doi.org/10.1016/S0076-6879(96)72006-2
  15. Guengerich, F. P. and Shimada, T., Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes. Chem. Res. Toxicol., 4, 391-407 (1991) https://doi.org/10.1021/tx00022a001
  16. Inouye, K., Saito, A., Orita, M., Tonomura, B., Imaishi, H., and Ohkawa, H., Inhibitory effects of 1,4-naphthoquinone deriva-tives on rat cytochrome P4501A1-dependent monooxygenase activity in recombinant yeast microsomes. J. Biochem., 127, 1041-1046 (2000) https://doi.org/10.1093/oxfordjournals.jbchem.a022695
  17. Jean, P., Lopez-Garcia, P., Dansette, P., Mansuy, D., and Goldstein, J. L., Oxidation of tienilic acid by human yeast-expressed cytochromes P-450 2C8, 2C9, 2C18 and 2C19. Evidence that this drug is a mechanism-based inhibitor specific for cytochrome P-450 2C9. Eur. J. Biochem., 241, 797-804 (1996) https://doi.org/10.1111/j.1432-1033.1996.00797.x
  18. Kim, S., Ko, H., Park, J. E., Jung, S., Lee, S. K., and Chun, Y. J., Design, synthesis, and discovery of novel trans-stilbene analogues as potent and selective human cytochrome P450 1B1 inhibitors. J. Med. Chem., 45, 160-164 (2002a) https://doi.org/10.1021/jm010298j
  19. Kim, Y. M., Yun, J., Lee, C. K., Lee, H., Min, K. R., and Kim, Y., Oxyresveratrol and hydroxystilbene compounds. Inhibitory effect on tyrosinase and mechanism of action. J. Biol. Chem., 277, 16340-16344 (2002b) https://doi.org/10.1074/jbc.M200678200
  20. Kleiner, H. E., Vulimiri, S. V., Reed, M. J., Uberecken, A., and DiGiovanni, J., Role of cytochrome P450 1a1 and 1b1 in the metabolic activation of 7,12-dimethylbenz[a]anthracene and the effects of naturally occurring furanocoumarins on skin tumor initiation. Chem. Res. Toxicol., 15, 226-235 (2002) https://doi.org/10.1021/tx010151v
  21. Koenigs, L. L., Peter, R. M., Hunter, A. P., Haining, R. L., Rettie, A. E., Friedberg, T., Pritchard, M. P., Shou, M., Rushmore, T. H., and Trager, W. F, Electrospray ionization mass spectrometric analysis of intact cytochrome P450: identification of tienilic acid adducts to P450 2C9. Biochemistry, 38, 2312-2319(1999) https://doi.org/10.1021/bi9823030
  22. Mays, D., Hilliard, J., Wong, D., Chambers, M., Park, S., Gelboin, H., and Gerber, N., Bioactivation of 8-methoxypsoralen and irreversible inactivation of cytochrome P-450 in mouse liver microsomes: modification by monoclonal antibodies, inhibition of drug metabolism and distribution of covalent adducts. J. Pharmacol. Exp. Ther., 254, 720-731 (1990)
  23. Nimmanpisut, S., Chudapongse, P., and Ratanabanangkoon, K., Effects of 2,4,3',5'-tetrahydroxystilbene on oxidative phos-phorylation by rat liver mitochondria. Biochem. Pharmacol., 25, 1245-1248 (1976) https://doi.org/10.1016/0006-2952(76)90085-X
  24. Obach, R. S., Inhibition of human cytochrome P450 enzymes by constituents of St. John's Wort, an herbal preparation used in the treatment of depression. J. Pharmacol. Exp. Ther., 294, 88-95 (2000)
  25. O'Donnell, J. P., Dalvie, D. K., Kalgutkar, A. S., and Obach, R. S., Mechanism-based inactivation of human recombinant P450 2C9 by the nonsteroidal anti-inflammatory drug suprofen. Drug Metab. Dispos., 31, 1369-1377 (2003) https://doi.org/10.1124/dmd.31.11.1369
  26. Omura, T. and Sato, R., The carbon-monoxide binding pigment of liver microsomes. J. Biol. Chem., 239, 2370-2378 (1964)
  27. Parikh, A., Gillam, E. M., and Guengerich, F. P., Drug metabolism by Escherichia coli expressing human cytochromes P450. Nat. Biotechnol., 15, 784-788 (1997) https://doi.org/10.1038/nbt0897-784
  28. Pervaiz, S., Resveratrol: from grapevines to mammalian biology. FASEB J., 17, 1975-1985 (2003) https://doi.org/10.1096/fj.03-0168rev
  29. Schwarz, D., Kisselev, P., and Roots, I., St. John's wort extracts and some of their constituents potently inhibit ultimate carcinogen formation from benzo[a]pyrene-7,8-dihydrodiol by human CYP1A1. Cancer Res., 63, 8062-8068 (2003)
  30. Shimada, T., Yamazaki, H., Foroozesh, M., Hopkins, N. E., Alworth, W. L., and Guengerich, F. P., Selectivity of polycyclic inhibitors for human cytochrome P450s 1A1, 1A2, and 1B1. Chem. Res. Toxicol., 11, 1048-1056 (1998) https://doi.org/10.1021/tx980090+
  31. Shin, N. H., Ryu, S. Y., Choi, E. J., Kang, S. H., Chang, I. M., Min, K. R., and Kim, Y., Oxyresveratrol as the potent inhibitor on dopa oxidase activity of mushroom tyrosinase. Biochem. Biophys. Res. Commun., 243, 801-803 (1998a) https://doi.org/10.1006/bbrc.1998.8169
  32. Shin, N. H., Ryu, S. Y., Lee, H., Min, K. R., and Kim, Y., Inhibitory effects of hydroxystilbenes on cyclooxygenase from sheep seminal vesicles. Planta Med., 64, 283-284 (1998b) https://doi.org/10.1055/s-2006-957430
  33. Zhai, S., Dai, R., Friedman, F. K., and Vestal, R. E., Comparative inhibition of human cytochromes P450 1A1 and 1A2 by flavonoids. Drug Metab. Dispos., 26, 989-992 (1998)