In vivo effects of genistein, herbimycin a and geldanamycin on rat hepatic cytochrome P4501A


Cytochrome P4501A (the CYP1A1 and CYP1A2 enzymes) are regulated through the aryl hydrocarbon receptor (AhR)-dependent signal transduction pathway and are generally known as enzymes which metabolize anthropogenic xenobiotics such as dioxin to carcinogenic and mutagenic compounds. However, recently the facts of CYP1A activation under physiological conditions or under action of non-dioxin-like compounds appear. In the present study we show that genistein, herbimycin A and geldanamycin (the protein-tyrosine kinase inhibitors) affect in vivo to CYP1A1 activity, the CYP1A1 mRNA level and the CYP1A1 protein level. These data provide insight into the role of protein kinases in CYP1A regulation may facilitate the understanding of CYP1A regulation.

Share and Cite:

L. Perepechaeva, M. and Y. Grishanova, A. (2012) In vivo effects of genistein, herbimycin a and geldanamycin on rat hepatic cytochrome P4501A. Journal of Biophysical Chemistry, 3, 334-340. doi: 10.4236/jbpc.2012.34041.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Denison, M.S. and Nagy, S.R. (2003) Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annual Review of Pharmacology and Toxicology, 43, 309-334. doi:10.1146/annurev.pharmtox.43.100901.135828
[2] Ma, Q. (2001) Induction of CYP1A1. The AhR/DRE paradigm: Transcription, receptor regulation, and expanding biological roles. Current Drug Metabolism, 2, 149-164. doi:10.2174/1389200013338603
[3] Enan, E. and Matsumura, F. (1996) Identification of c-Src as the integral component of the cytosolic Ah receptor complex, transducing the signal of 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) through the protein phosphorylation pathway. Biochemical Pharmacology, 52, 1599-1612. doi:10.1016/S0006-2952(96)00566-7
[4] Fujii-Kuriyama, Y. and Kawajiri, K. (2010) Molecular mechanisms of the physiological functions of the aryl hydrocarbon (dioxin) receptor, a multifunctional regulator that senses and responds to environmental stimuli. Proceedings of the Japan Academy, Series B, Physical and biological sciences, 86, 40-53. doi:10.2183/pjab.86.40
[5] Ma, C., Marlowe, J.L. and Puga, A. (2009) The aryl hydrocarbon receptor at the crossroads of multiple signaling pathways. Experientia Supplementum, 99, 231-257. doi:10.1007/978-3-7643-8336-7_9
[6] Delescluse, C., Lemaire, G., de Sousa, G., and Rahmani, R. (2000) Is CYP1A1 induction always related to AHR signaling pathway? Toxicology, 153, 73-82. doi:10.1016/S0300-483X(00)00305-X
[7] Levine, S.L. and Perdew, G.H. (2001) Aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) activity is unaltered by phosphorylation of a periodicity/ARNT/ single-minded (PAS)-region serine residue. Molecular Pharmacology, 59, 557-566.
[8] Oesch-Bartlomowicz, B. and Oesch, F. (2004) Modulation of mutagenicity by phosphorylation of mutagenmetabolizing enzymes. Archives of Biochemistry and Biophysics, 423, 31-36. doi:10.1016/
[9] Oesch-Bartlomowicz, B. and Oesch, F. (2005) Phosphorylation of cytochromes P450: First discovery of a posttranslational modification of a drug-metabolizing enzyme. Biochemical and Biophysical Research Communications, 338, 446-449. doi:10.1016/j.bbrc.2005.08.092
[10] Robinson, D.R., Wu, Y.M. and Lin, S.F. (2000) The protein tyrosine kinase family of the human genome. Oncogene, 19, 5548-5557. doi:10.1038/sj.onc.1203957
[11] Vlahovic, G. and Crawford, J. (2003) Activation of tyrosine kinases in cancer. Oncologist, 8, 531-538. doi:10.1634/theoncologist.8-6-531
[12] Burke, M.D., Thompson, S., Elcombe, C.R., Halpert, J., Haaparanta, T. and Mayer, R.T. (1985) Ethoxy-, pentoxy- and benzyloxyphenoxazones and homologues: A series of substrates to distinguish between different induced cytochromes P-450. Biochemical Pharmacology, 34, 3337-3345. doi:10.1016/0006-2952(85)90355-7
[13] Lowry, O.H., Rosebrough, N.J., Farr, A.L. and Randall, R.J. (1951) Protein measurement with the Folin phenol reagent. The Journal of Biological Chemistry, 193, 265- 275.
[14] Morris, D.L. and Davila, J.C. (1996) Analysis of rat cytochrome P450 isoenzyme expression using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Biochemical pharmacology, 52, 781-792. doi:10.1016/0006-2952(96)00390-5
[15] Walker, N.J., Portier, C.J., Lax, S.F., Crofts, F.G. Li, Y., Lucier, G.W. and Sutter, T.R. (1999) Characterization of the dose-response of CYP1B1, CYP1A1, and CYP1A2 in the liver of female Sprague-dawley rats following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology and Applied Pharmacology, 154, 279-286. doi:10.1006/taap.1998.8595
[16] Adams, N.H., Levi, P.E., and Hodgson, E. (1993) Regulation of cytochrome P-450 isozymes by methylenedioxyphenyl compounds. Chemico-Biological Interactions, 86, 255-274. doi:10.1016/0009-2797(93)90101-4
[17] Laemmli, U.K. (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 227, 680-685. doi:10.1038/227680a0
[18] Grishanova, A.Yu and Lyakhovich, V.V. (1992) Using of antibodies to cytochrome P-450 library in xenobiotics metabolism studies. In: Archakov, A. and Bachmanova, G., Eds., Cytochrome P-450: Biоchemistry and Вiophysics, INCO-TNC, Moscow, 525-528.
[19] Schirmer, K., Chan, A.G. and Bols, N.C. (2000) Transitory metabolic disruption and cytotoxicity elicited by benzo[a]pyrene in two cell lines from rainbow trout liver. Journal of Biochemical and Molecular Toxicology, 14, 262-276. doi:10.1002/1099-0461(2000)14:5<262::AID-JBT5>3.0.CO;2-2
[20] Lemaire, G., Delescluse, C., Pralavorio, M., Ledirac, N., Lesca, P. and Rahmani, R. (2004) The role of protein tyrosine kinases in CYP1A1 induction by omeprazole and thiabendazole in rat hepatocytes. Life Sciences, 74, 2265-2278. doi:10.1016/j.lfs.2003.09.056
[21] Kikuchi, H., Hossain, A., Yoshida, H. and Kobayashi, S. (1998) Induction of cytochrome P-450 1A1 by omeprazole in human HepG2 cells is protein tyrosine kinase-dependent and is not inhibited by alpha-naphthoflavone. Archives of Biochemistry and Biophysics, 358, 351-358. doi:10.1006/abbi.1998.0869
[22] Wiseman, S.B. and Vijayan, M.M. (2007) Aryl hydrocarbon receptor signaling in rainbow trout hepatocytes: Role of hsp90 and the proteasome. Comparative Biochemistry and Physiology, Part C, 146, 484-491.
[23] Song, Z. and Pollenz, R.S. (2002) Ligand-dependent and independent modulation of aryl hydrocarbon receptor localization, degradation, and gene regulation. Molecular Pharmacology, 62, 806-816. doi:10.1124/mol.62.4.806
[24] Hoelper, P., Faust, D., Oesch, F. and Dietrich, C. (2005) Evaluation of the role of c-Src and ERK in TCDD-dependent release from contact-inhibition in WB-F344 cells. Archives of Toxicology, 79, 201-207. doi:10.1007/s00204-004-0624-6
[25] Shertzer, H.G., Puga, A., Chang, C., Smith, P., Nebert, D.W., Setchell, K.D. and Dalton, T.P. (1999) Inhibition of CYP1A1 enzyme activity in mouse hepatoma cell culture by soybean isoflavones. Chemico-Biological Interactions, 123, 31-49. doi:10.1016/S0009-2797(99)00121-0
[26] Backlund, M., Johansson, I., Mkrtchian, S. and Ingelman-Sundberg, M. (1997) Signal transduction-mediated activation of the aryl hydrocarbon receptor in rat hepatoma H4IIE cells. The Journal of Biological Chemistry, 272, 31755-31763.
[27] Gradin, K., Whitelaw, M.L., Toftgard, R., Poellinger, L. and Berghard, A. (1994) A tyrosine kinase-dependent pathway regulates ligand-dependent activation of the dioxin receptor in human keratinocytes. The Journal of Biological Chemistry, 269, 23800-23807.
[28] Rowlands, J.C., He, L., Hakkak, R., Ronis, M.J. and Badger, T.M. (2001) Soy and whey proteins downregulate DMBA-induced liver and mammary gland CYP1 expression in female rats. The Journal of Nutrition, 131, 3281- 3287.
[29] Harper, P.A., Riddick, D.S. and Okey, A.B. (2006) Regulating the regulator: Factors that control levels and activity of the aryl hydrocarbon receptor. Biochemical Pharmacology, 72, 267-279. doi:10.1016/j.bcp.2006.01.007
[30] Sidorova, Y.A., Grishanova, A.Y. and Lyakhovich, V.V. (2004) Transcriptional activation of cytochrome P450 1A1 with alpha-tocopherol. Bulletin of Experimental Biology and Medicine, 138, 233-236.
[31] Sidorova, Y.A., Grishanova, A.Y. and Lyakhovich, V.V. (2005) Rat hepatic CYP1A1 and CYP1A2 induction by menadione. Toxicology Letters, 155, 253-258. doi:10.1016/j.toxlet.2004.10.001
[32] Sidorova, Y.A. and Grishanova, A.Y. (2005) Inhibitory effect of alpha-tocopherol on benzo(a)pyrene-induced CYPA1 activity in rat liver. Bulletin of Experimental Biology and Medicine, 140, 517-520. doi:10.1007/s10517-006-0012-8
[33] Whitlock J.P.Jr. (1999) Induction of cytochrome P4501- A1. Annual Review of Pharmacology and Toxicology, 39, 103-125. doi:10.1146/annurev.pharmtox.39.1.103
[34] Quattrochi, L.C., Vu, T. and Tukey, R.H. (1994) The human CYP1A2 gene and induction by 3-methyl-cholanthrene. A region of DNA that supports AH-receptor binding and promoter-specific induction. The Journal of Biological Chemistry, 269, 6949-6954.
[35] Raffalli-Mathieu, F. Geneste, O. and Lang, M.A. (1997) Characterization of two nuclear proteins that interact with cytochrome P-450 1A2 mRNA. Regulation of RNA binding and possible role in the expression of the CYP1A2 gene. European Journal of Biochemistry, 245, 17-24. doi:10.1111/j.1432-1033.1997.00017.x

Copyright © 2021 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.