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Antiestrogenic effects of marijuana smoke condensate and cannabinoid compounds

Abstract

The antiestrogenic effects of marijuana smoke condensate (MSC) and three major cannab-inoids, i.e., Δ9-Metrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN), were evaluated usingin 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-O-deethylase (EROD) assay, the aromatase assay, and the 17β-estradiol (E2) metabolism assay. The results showed that MSC induced the antiestrogenic effectvia 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 E2 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 thein situ E2 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.

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References

  • Arcara, 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).

    Article  Google Scholar 

  • Ashton, H., Adverse effects of cannabis and cannabinoids: a review.Br. J. Anaesth., 83, 637–649 (1999).

    PubMed  CAS  Google Scholar 

  • Berstein, L. M., Tsyrlina, E. V, Krjukova, O. G, and Dzhumasultanova, S. V., Influence of tobacco smoke on DNA unwinding and uterotrophic effect of estrogens in rats.Cancer Lett., 127, 95–98 (1998).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Bradlow, H. L, Telang, N. T., Sepkovic, D. W., and Osborne, M. P., 2-hydroxyestrone: the ’good’ estrogen: a review.J. Endocrino!., 150, S259-S265 (1996).

    CAS  Google Scholar 

  • Brown, T. T. and Dobs, A. S., Endocrine effects of marijuana: a review.J. Clin. Pharmacol., 42, 90S-96S (2002).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Drenth, H. J., Bouwman, C. A., Seinen, W., and Van denBerg, M., Effects of some persistent halogenated environmental contaminants on aromatase (CYP19) activity in the human choriocarcinoma cell line JEG-3.Toxicol. Appi. Pharmacol., 148, 50–55(1998).

    Article  CAS  Google Scholar 

  • 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., Phytochemical-induced changes in gene expression of carcinogen-metabolizing enzymes in cultured human primary hepatocytes.Xenobiotica, 34, 619–632 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Hasselberg, L., Meier, S., Svardal, A., Hegelund, T., and Celander, M. Effects of alkylphenols on CYP1A and CYP3A expression in first spawning Atlantic cod (Gadus morhua).Aquat. Toxicol., 67, 303–313 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Hummerich, J., Zohm, C., and Pfau, W., Modulation of cytochrome P450 1A1 by food-derived heterocyclic aromatic amines.Toxicology, 199, 231–240 (2004).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Korach, 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).

  • Kuiper, G. G., Lemmen, J. G., Carlsson, Corton J. C., Safe S. H., Van DerSaag, P. T., Van DerBurg, B., and Gustafsson, J. A., Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta.Endocrinology, 139, 4252–4263 (1998).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  CAS  Google Scholar 

  • Martin, B. R., Cellular effects of cannabinoids.Pharmacol. Rev., 38, 45–74 (1986).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Mueck, A. O. and Seeger, H., Smoking, estradiol metabolism and hormone replacement therapy.Curr. Med. Chem. Cardiovasc. Hematol. Agents, 3, 45–54 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Nahas, G., and Latour, C., The human toxicity of marijuana: a review.Med. J. Aust, 156, 495–497 (1992).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Robert, M. J., A primer of drug action. Fifth Edition. W. H. Freeman and Company, New York, (1988).

    Google Scholar 

  • Rosenkrantz, H. and Esber, H. J., Cannabinoid-induced hormone changes in monkeys and rats.J. Toxicol. Environ. Health., 6, 297–313 (1980).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Safe, S. and Wormke, M., Inhibitory aryl hydrocarbon receptor-estrogen receptor alpha cross-talk and mechanisms of action: a review.Chem. Res. Toxicol., 16, 807–816 (2003).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Smith, R. 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).

    PubMed  CAS  Google Scholar 

  • Smith, 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Spangler, J. G., Smoking and hormone-related disorders.Prim. Care, 26, 499–511 (1999).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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 polycydic aromatic hydrocarbons (PAH) and nitroin coke oven emission extract.Mutat. Res., 419, 91–105 (1998).

    PubMed  CAS  Google Scholar 

  • Tran, D. Q., Ide, 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).

    PubMed  CAS  Google Scholar 

  • Tsuchiya, Y., Nakajima, M., and Yokoi, T., Cytochrome 450-mediated metabolism of estrogens and its regulation in human.CancerLett., 227, 115–124 (2005).

    CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Kyu Hyuck Chung.

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Lee, S.Y., Oh, S.M., Lee, S.K. et al. Antiestrogenic effects of marijuana smoke condensate and cannabinoid compounds. Arch Pharm Res 28, 1365–1375 (2005). https://doi.org/10.1007/BF02977903

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