Antiestrogenic Effects of Marijuana Smoke Condensate and Cannabinoid Compounds

  • Lee Soo Yeun (National Institute of Scientific Investigation, College of Pharmacy, Sungkyunkwan University) ;
  • Oh Seung Min (College of Pharmacy, Sungkyunkwan University) ;
  • Lee Sang Ki (National Institute of Scientific Investigation) ;
  • Chung Kyu Hyuck (College of Pharmacy, Sungkyunkwan University)
  • Published : 2005.12.01

Abstract

The antiestrogenic effects of marijuana smoke condensate (MSC) and three major cannabinoids, i.e., $\bigtriangleup^{9}$-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN), were evaluated using in vitro bioassays, viz., the human breast cancer cell proliferation assay, the recombinant human estrogen receptor (ER) competitive binding assay, and the reporter gene assay. The inhibitory effects on estrogen were also examined using the ethoxyresorufin-O­deethylase (EROD) assay, the aromatase assay, and the 17$\beta$-estradiol ($E_{2}$) metabolism assay. The results showed that MSC induced the antiestrogenic effect via the ER-mediated pathway, while THC, CBD, and CBN did not have any antiestrogenic activity. This suggests that the combined effects of the marijuana smoke components are responsible for the antiestrogenicity of marijuana use. In addition, MSC induced the CYP1A activity and the $E_{2}$ metabolism, but inhibited the aromatase activity, suggesting that the antiestrogenic activity of MSC is also related to the indirect ER-dependent pathway, as a result of the depletion of the in situ $E_{2}$ level available to bind to the ER. In conclusion, pyrogenic products including polycyclic aromatic hydrocarbons (PAHs) in the non-polar fraction, which is the most biologically active fraction among the seven fractions of MSC, might be responsible for the antiestrogenic effect.

Keywords

References

  1. Arcaro, K. F., O'Keefe, P. W., Yang, Y., Clayton, W., and Gierthy, J. F., Antiestrogenicity of environmental polycyclic aromatic hydrocarbons in human breast cancer cells. Toxicology, 133,115-127 (1999) https://doi.org/10.1016/S0300-483X(99)00018-9
  2. Ashton, C. H., Adverse effects of cannabis and cannabinoids: a review. Br. J. Anaesth., 83, 637-649 (1999) https://doi.org/10.1093/bja/83.4.637
  3. Moon, C. H., Kim, M. Y., Kim, M. J., Kim, M. H., Lee, S., Yi, K. Y., Yoo, S. E., Lee, D. H., Lim, H., Kim, H. S., Lee, S. H., Baik, E. J., and Jung, Y. S., Influence of tobacco smoke on DNA unwinding and uterotrophic effect of estrogens in rats. Cancer Lett., 127, 95-98 (1998) https://doi.org/10.1016/S0304-3835(98)00012-3
  4. Bradford, M., A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 72, 248-254 (1976) https://doi.org/10.1016/0003-2697(76)90527-3
  5. Bradlow, H. L., Telang, N. T., Sepkovic, D. W., and Osborne, M. P., 2-hydroxyestrone: the 'good' estrogen: a review. J. Endocrinol., 150, S259-S265 (1996)
  6. Brown, T. T. and Dobs, A. S., Endocrine effects of marijuana: a review. J. Clin. Pharmacol., 42, 90S-96S (2002) https://doi.org/10.1002/j.1552-4604.2002.tb06008.x
  7. Chaloupka, K., Krishnan, V., and Safe, S., Polynuclear aromatic hydrocarbon carcinogens as antiestrogens in MCF-7 human breast cancer cells: role of the Ah receptor. Carcinogenesis, 13, 2233-2239 (1992) https://doi.org/10.1093/carcin/13.12.2233
  8. Chung, H., Park, M., Hahn, E., Choi, H., Choi, H., and Lim, M., Recent trends of drug abuse and drug-associated deaths in Korea. Ann. N. Y. Acad. Sci., 1025, 458-464 (2004) https://doi.org/10.1196/annals.1316.056
  9. Dannan, G. A., Porubek, D. J., Nelson, S. D., Waxman, D. J., and Guengerich, F.P., 17 Beta-estradiol 2- and 4-hydroxylation catalyzed by rat hepatic cytochrome P-450: roles of individual forms, inductive effects, developmental patterns, and alterations by gonadectomy and hormone replacement. Endocrinology, 118, 1952-1960 (1986) https://doi.org/10.1210/endo-118-5-1952
  10. Drenth, H. J., Bouwman, C. A., Seinen, W., and Van den Berg, M., Effects of some persistent halogenated environmental contaminants on aromatase (CYP19) activity in the human choriocarcinoma cell line JEG-3. Toxicol. Appl. Pharmacol., 148, 50-55 (1998) https://doi.org/10.1006/taap.1997.8307
  11. Gross-Steinmeyer, K., Stapleton, P. L., Liu, F., Tracy, J. H., Bammler, T. K., Quigley, S. D., Farin, F. M., Buhler, D. R., Safe, S. H., Strom, S. C., and Eaton, D. L., Phytochemicalinduced changes in gene expression of carcinogenmetabolizing enzymes in cultured human primary hepatocytes. Xenobiotica, 34, 619-632 (2004) https://doi.org/10.1080/00498250412331285481
  12. Hasselberg, L., Meier, S., Svardal, A., Hegelund, T., and Celander, M. C., Effects of alkylphenols on CYP1A and CYP3A expression in first spawning Atlantic cod (Gadus morhua). Aquat. Toxicol., 67, 303-313 (2004) https://doi.org/10.1016/j.aquatox.2003.12.007
  13. Hummerich, J., Zohm, C., and Pfau, W., Modulation of cytochrome P450 1A1 by food-derived heterocyclic aromatic amines. Toxicology, 199, 231-240 (2004) https://doi.org/10.1016/j.tox.2004.02.028
  14. Iba, M. M., Nguyen, T., and Fung, J., CYP1A1 induction by pyridine and its metabolites in HepG2 cells. Arch. Biochem. Biophys., 404, 326-334 (2002) https://doi.org/10.1016/S0003-9861(02)00332-6
  15. Kamiya, M., Toriba, A., Onoda, Y., Kizu, R., and Hayakawa, K., Evaluation of estrogenic activities of hydroxylated polycyclic aromatic hydrocarbons in cigarette smoke condensate. Food Chem. Toxicol., 43, 1017-1027 (2005) https://doi.org/10.1016/j.fct.2005.02.004
  16. Korach, K. S., Davis, V. L., Curtis, S. W., and Bocchinfuso, W. P., Xenoestrogens and estrogen receptor action, In Thomas, J. A., and Colby, H. D. (Eds.). Endocrine Toxicology. Talylor & Francis, pp. 181-205, (1997)
  17. Kuiper, G. G., Lemmen, J. G., Carlsson, B., Corton J. C., Safe S. H., Van Der Saag, P. T., Van Der Burg, B., and Gustafsson, J. A., Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology, 139, 4252-4263 (1998) https://doi.org/10.1210/en.139.10.4252
  18. Lewtas, J., Chuang, J., Nishioka, M., and Peterson, B., Bioassay-directed fractionation of the organic extract of SRM 1649 urban air particulate matter. Int. J. Environ. Anal. Chem. 39, 245-256 (1990) https://doi.org/10.1080/03067319008032068
  19. Martin, B. R., Cellular effects of cannabinoids. Pharmacol. Rev., 38, 45-74 (1986)
  20. Meek, M. D. and Finch, G. L., Diluted mainstream cigarette smoke condensates activate estrogen receptor and aryl hydrocarbon receptor-mediated gene transcription. Environ. Res., 80, 9-17 (1999) https://doi.org/10.1006/enrs.1998.3872
  21. Mueck, A. O. and Seeger, H., Smoking, estradiol metabolism and hormone replacement therapy. Curr. Med. Chem. Cardiovasc. Hematol. Agents, 3, 45-54 (2005) https://doi.org/10.2174/1568016052773270
  22. Nahas, G. and Latour, C., The human toxicity of marijuana: a review. Med. J. Aust., 156, 495-497 (1992)
  23. Perez, P., Pulgar, R., Olea-Serrano, F., Villalobos, M., Rivas, A., Metzler, M., Pedraza, V., and Olea, N., The estrogenicity of bisphenol A-related diphenylalkanes with various substituents at the central carbon and the hydroxy groups. Environ. Health. Perspect., 106, 167-174 (1998) https://doi.org/10.2307/3434318
  24. Porter, W. and Safe, S. H, Estrogenic and antiestrogenic compounds, In Puga, A., and Wallace, K. B. (Eds.). Molecular biology of the toxic response. Talylor & Francis, pp. 267-279, (1999)
  25. Rawitch, A. B., Schultz, G. S., Ebner, K. E., and Vardaris, R. M., Competition of delta 9-tetrahydrocannabinol with estrogen in rat uterine estrogen receptor binding. Science, 197, 1189- 1191 (1977) https://doi.org/10.1126/science.897662
  26. Robert, M. J., A primer of drug action. Fifth Edition. W. H. Freeman and Company, New York, (1988)
  27. Rawitch, A. B., Schultz, G. S., Ebner, K. E., and Vardaris, R. M., Cannabinoid-induced hormone changes in monkeys and rats. J. Toxicol. Environ. Health., 6, 297-313 (1980) https://doi.org/10.1080/15287398009529853
  28. Roth, M. D., Marques-Magallanes, J. A., Yuan, M., Sun, W., Tashkin, D. P., and Hankinson, O., Induction and regulation of the carcinogen-metabolizing enzyme CYP1A1 by marijuana smoke and delta (9)-tetrahydrocannabinol. Am. J. Respir. Cell Mol. Biol., 24, 339-344 (2001) https://doi.org/10.1165/ajrcmb.24.3.4252
  29. Ruh, M. F., Taylor, J. A., Howlett, A. C., and Welshons, W. V., Failure of cannabinoid compounds to stimulate estrogen receptors. Biochem. Pharmacol., 53, 35-41 (1997) https://doi.org/10.1016/S0006-2952(96)00659-4
  30. Safe, S. and Wormke, M., Inhibitory aryl hydrocarbon receptorestrogen receptor alpha cross-talk and mechanisms of action: a review. Chem. Res. Toxicol., 16, 807-816 (2003) https://doi.org/10.1021/tx034036r
  31. Sauer, M. A., Rifka, S. M., Hawks, R. L., Cutler, G.. B. Jr., and Loriaux, D. L., Marijuana: interaction with the estrogen receptor. J. Pharmacol. Exp. Ther., 224, 404-407 (1983)
  32. Schneider, J., Huh, M.M., Bradlow, H. L., and Fishman, J., Antiestrogen action of 2-hydroxyestrone on MCF-7 human breast cancer cells. J. Biol. Chem., 259, 4840-4845 (1984)
  33. Shou, M., Korzekwa, K. R., Brooks, E. N., Krausz, K. W., Gonzalez, F. J., and Gelboin, H. V., Role of human hepatic cytochrome P450 1A2 and 3A4 in the metabolic activation of estrone. Carcinogenesis, 18, 207-214 (1997) https://doi.org/10.1093/carcin/18.1.207
  34. Smith, C. G. and Asch, R. H., Acute, short-term, and chronic effects of marijuana on the female primate reproductive function. NIDA Res. Monogr., 44, 82-96 (1984)
  35. Smith, C. J., Qian, X., Zha, Q., and Moldoveanu, S. C., Analysis of alpha- and beta-carbolines in mainstream smoke of reference cigarettes by gas chromatography-mass spectrometry. J. Chromatogr. A, 1046, 211-216 (2004) https://doi.org/10.1016/S0021-9673(04)01030-1
  36. Smith, R. G., Besch, N. F., Besch, P. K., and Smith, C. G., Inhibition of gonadotropin by delta9-tetrahydrocannabinol : mediation by steroid receptors? Science, 204, 325-327 (1979) https://doi.org/10.1126/science.107589
  37. Spangler, J. G., Smoking and hormone-related disorders. Prim. Care, 26, 499-511 (1999) https://doi.org/10.1016/S0095-4543(05)70114-7
  38. Spink, D. C., Eugster, H. P., Lincoln, D. W. 2nd, Schuetz, J. D., Schuetz, E. G., Johnson, J. A., Kaminsky, L. S., and Gierthy, J. F., 17 Beta-estradiol hydroxylation catalyzed by human cytochrome P450 1A1: a comparison of the activities induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in MCF-7 cells with those from heterologous expression of the cDNA. Arch. Biochem. Biophys., 293, 342-348 (1992) https://doi.org/10.1016/0003-9861(92)90404-K
  39. Suchar, L. A., Chang, R. L., Rosen, R. T., Lech, J., and Conney, A. H., High-performance liquid chromatography separation of hydroxylated estradiol metabolites: formation of estradiol metabolites by liver microsomes from male and female rats. J. Pharmacol. Exp. Ther., 272, 197-206 (1995)
  40. Szaefer, H., Jodynis-Liebert, J., Cichocki, M., Matuszewska, A., and Baer-Dubowska, W., Effect of naturally occurring plant phenolics on the induction of drug metabolizing enzymes by o-toluidine. Toxicology, 186, 67-77 (2003) https://doi.org/10.1016/S0300-483X(02)00615-7
  41. Tanaka, S., Haji, M., Takayanagi, R., Tanaka, S., Sugioka, Y., and Nawata, H., 1,25-Dihydroxyvitamin D3 enhances the enzymatic activity and expression of the messenger ribonucleic acid for aromatase cytochrome P450 synergistically with dexamethasone depending on the vitamin D receptor level in cultured human osteoblasts. Endocrinology, 137, 1860-1869 (1996) https://doi.org/10.1210/en.137.5.1860
  42. Topinka, J., Schwarz, L. R., Kiefer, F., Wiebel, F. J., Gajdos, O., Vidova, P., Dobias, L., Fried, M., Sram, R. J., and Wolff, T., DNA adduct formation in mammalian cell cultures by polycyclic aromatic hydrocarbons (PAH) and nitro-PAH in coke oven emission extract. Mutat. Res., 419, 91-105 (1998) https://doi.org/10.1016/S1383-5718(98)00127-2
  43. Tran, D. Q., Ide, C.,F., McLachlan, J. A., and Arnold, S. F., The anti-estrogenic activity of selected polynuclear aromatic hydrocarbons in yeast expressing human estrogen receptor. Biochem. Biophys. Res. Commun., 229, 101-108 (1996) https://doi.org/10.1006/bbrc.1996.1764
  44. Tsuchiya, Y., Nakajima, M., and Yokoi, T., Cytochrome P450- mediated metabolism of estrogens and its regulation in human. Cancer Lett., 227, 115-124 (2005) https://doi.org/10.1016/j.canlet.2004.10.007
  45. Watanabe, K., Motoya, E., Matsuzawa, N., Funahashi, T., Kimura, T., Matsunaga, T., Arizono, K., and Yamamoto, I.,Marijuana extracts possess the effects like the endocrine disrupting chemicals. Toxicology, 206, 471-478 (2005) https://doi.org/10.1016/j.tox.2004.08.005
  46. Yamazaki, H., Shaw, P. M., Guengerich, F. P., and Shimada, T., Roles of cytochromes P450 1A2 and 3A4 in the oxidation of estradiol and estrone in human liver microsomes. Chem. Res. Toxicol., 11, 659-665 (1998) https://doi.org/10.1021/tx970217f