Browse > Article

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)
Publication Information
Archives of Pharmacal Research / v.28, no.12, 2005 , pp. 1365-1375 More about this Journal
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
Marijuana; Cannabinoids; Drug abuse; Antiestrogenic effects; Polycyclic aromatic hydrocarbons (PAHs);
Citations & Related Records

Times Cited By Web Of Science : 2  (Related Records In Web of Science)
Times Cited By SCOPUS : 2
연도 인용수 순위
1 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)   DOI   PUBMED   ScienceOn
2 Brown, T. T. and Dobs, A. S., Endocrine effects of marijuana: a review. J. Clin. Pharmacol., 42, 90S-96S (2002)   DOI
3 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)   DOI   PUBMED   ScienceOn
4 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)   DOI   ScienceOn
5 Robert, M. J., A primer of drug action. Fifth Edition. W. H. Freeman and Company, New York, (1988)
6 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)
7 Spangler, J. G., Smoking and hormone-related disorders. Prim. Care, 26, 499-511 (1999)   DOI   PUBMED
8 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)
9 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)   DOI   PUBMED   ScienceOn
10 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)   DOI   ScienceOn
11 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)   DOI   ScienceOn
12 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)   DOI   ScienceOn
13 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)   DOI   ScienceOn
14 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)   DOI   ScienceOn
15 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)   DOI   ScienceOn
16 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)   DOI   ScienceOn
17 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)
18 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)   DOI   PUBMED
19 Mueck, A. O. and Seeger, H., Smoking, estradiol metabolism and hormone replacement therapy. Curr. Med. Chem. Cardiovasc. Hematol. Agents, 3, 45-54 (2005)   DOI   ScienceOn
20 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)   DOI   ScienceOn
21 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)   DOI   ScienceOn
22 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)   DOI   ScienceOn
23 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)   DOI   ScienceOn
24 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)   DOI   ScienceOn
25 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)   DOI   ScienceOn
26 Hummerich, J., Zohm, C., and Pfau, W., Modulation of cytochrome P450 1A1 by food-derived heterocyclic aromatic amines. Toxicology, 199, 231-240 (2004)   DOI   PUBMED   ScienceOn
27 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)   DOI   PUBMED   ScienceOn
28 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)   DOI   ScienceOn
29 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)   DOI   PUBMED   ScienceOn
30 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)   DOI   ScienceOn
31 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)
32 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)   DOI   ScienceOn
33 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)   DOI   ScienceOn
34 Martin, B. R., Cellular effects of cannabinoids. Pharmacol. Rev., 38, 45-74 (1986)
35 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)
36 Ashton, C. H., Adverse effects of cannabis and cannabinoids: a review. Br. J. Anaesth., 83, 637-649 (1999)   DOI   ScienceOn
37 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)   DOI   PUBMED
38 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)   DOI   PUBMED
39 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)   DOI   ScienceOn
40 Nahas, G. and Latour, C., The human toxicity of marijuana: a review. Med. J. Aust., 156, 495-497 (1992)
41 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)   DOI   ScienceOn
42 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)   DOI   ScienceOn
43 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)
44 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)   DOI   ScienceOn
45 Tsuchiya, Y., Nakajima, M., and Yokoi, T., Cytochrome P450- mediated metabolism of estrogens and its regulation in human. Cancer Lett., 227, 115-124 (2005)   DOI   ScienceOn
46 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)