Potent inhibition of human cytochrome P450 1 enzymes by dimethoxyphenylvinyl thiophene
- 73 Downloads
Cytochrome P450 (P450) 1 enzymes such as P450 1A1, 1A2, and 1B1 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 theEscherichia 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 IC50 values of 61, 11, and 2 nM for 1A1, 1A2, and 1B1, respectively. The EROD activity in DMBA-treated rat lung microsomes was also significantly inhibited by DMPVT 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 DMPVT did not show the irreversible mechanism-based effect. The loss of EROD activity in P450 1B1 with DMPVT 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.
Key wordsCytochrome P450 1 enzyme Enzyme inhibitor Dimethoxyphenylvinyl thiophene
Unable to display preview. Download preview PDF.
- 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).PubMedCrossRefGoogle Scholar
- 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).Google Scholar
- 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).PubMedCrossRefGoogle Scholar
- 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).PubMedCrossRefGoogle Scholar
- 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).PubMedCrossRefGoogle Scholar
- 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).PubMedGoogle Scholar