Gap junctional communication

Imidazole antimycotics, ketoconazole, clotrimazole, and miconazole are potent inhibitors of various cytochrome P450-isoenzymes that also affect the metabolism of retinoids. They were fust shown to inhibit the metabolism of RA in F9 embryonal carcinoma cells. When tested in vitm liarazole, a potent CYP-inhibitor, suppressed neoplastic transformation and upregulated gap junctional communication in murine and human fibroblasts, which appeared to be due to the presence of retinoids in the serum component of the cell culture medium. Furthermore, liarazole magnified the cancer chemopreventive activity of RA and (3-carotene in these experiments by inhibiting RA-catabolism as demonstrated by absence of a decrease in RA-levels in the culture medium in the presence of liarazole over 48 h, whereas without liarazole 99% of RA was catabolized. In vivo, treatment with liarazole and ketoconazole reduced the accelerated catabolism of retinoids and increased the mean plasma all-irans-RA-concentration in patients with acute promyelocytic leukemia and other cancels. 

In the Unites States, the daily intake of 3-carotene is around 2 mg/day Several epidemiological studies have reported that consumption of carotenoid-rich foods is associated with reduced risks of certain chronic diseases such as cancers, cardiovascular disease, and age-related macular degeneration. These preventive effects of carotenoids may be related to their major function as vitamin A precursors and/or their actions as antioxidants, modulators of the immune response, and inducers of gap-junction communications. Not all carotenoids exert similar protective effects against specific diseases. By reason of the potential use of carotenoids as natural food colorants and/or for their health-promoting effects, research has focused on better understanding how they are absorbed by and metabolized in the human body. 

In atherosclerosis and other heart diseases, the role of carotenoids as antioxidants is probable, but for these types of diseases and also for other degenerative diseases such as cancers, non-antioxidant activities constitute other possible prevention mechanisms. These activities are, for example, stimulation of gap junction communications between cells, and the induction of detoxifying enzymes. The... 

Different types of apparently beneficial activities have been demonstrated in vitro for carotenoid oxidation products, including induction of gap-junctional communications, " growth inhibition of leukemia and cancer cells, induction of apoptosis... 

Stahl, W. and Sies, H., Effects of carotenoids and retinoids on gap junctional communication, Biofactors, 15, 95, 2001. 

The autoxidation of carotenoids in cell medium is highly probable when experiments are conducted over periods of a few hours. The autoxidation of canthaxanthin in a cell culture medium was shown to give all-( )- and 13-(Z)-4-oxoretinoic acid, both of which were shown to induce gap junction communication (Hanusch et al. 1995). 

Aust, O. et al. (2003). Lycopene oxidation product enhances gap junctional communication. Food Chem. Toxicol. 41(10) 1399-1407. 

Hanusch, M. et al. (1995). Induction of gap junctional communications by 4-oxoretinoic acid generated from its precursor canthaxanthin. Arch. Biochem. Biophys. 317(2) 423 -28. 

Stahl, W., Nicolai, S., Briviba, K., Hanusch, M., Broszeit,G., Peters, M., Martin, H.D., Sies, H., 1997. Biological activities of natural and synthetic carotenoids Induction of gap junctional communication and singlet oxygen quenching. Carcinogenesis. 18, 89-92. 

Hix, L. M., A. L. Vine, S. F. Lockwood, and J. S. Bertram. 2005. Retinoids and carotenoids as cancer chemo-preventive agents Role of upregulated gap junctional communication. In Carotenoids and Retinoids Molecular Aspects and Health Issues, edited by L. Packer, Obermueller-Jevic, U., Kraemer, K., and Sies, H. AOCS Press, Champaign, IL. 

Hossain, M. Z., L. R. Wilkens, P. P. Mehta, W. Loewenstein, and J. S. Bertram. 1989. Enhancement of gap junctional communication by retinoids correlates with their ability to inhibit neoplastic transformation. Carcinogenesis 10(9) 1743-1748. 

Livny, O., I. Kaplan, R. Reifen et al. 2002. Lycopene inhibits proliferation and enhances gap-junction communication of KB-1 human oral tumor cells. J Nutr 132(12) 3754—3759. 

Rogers, M., J. M. Berestecky, M. Z. Hossain et al. 1990. Retinoid-enhanced gap junctional communication is achieved by increased levels of connexin 43mRNA and protein. Mol Carcinog 3(6) 335-343. 

Stahl, W., J. von Laar, H. D. Martin, T. Emmerich, and H. Sies. 2000. Stimulation of gap junctional communication comparison of acyc/o-retinoic acid and lycopene. Arch Biochem Biophys 373(1 ) 271—274. 

Zhang, L. X., R. V. Cooney, and J. S. Bertram. 1991. Carotenoids enhance gap junctional communication and inhibit lipid peroxidation in C3H/10T1/2 cells Relationship to their cancer chemopreventive action. Carcinogenesis 12(11) 2109—2114. 

Hotz-Wagenblatt, A. and Shalloway, D. 1993. Gap junctional communication and neoplastic transformation. CritRev Oncog 4 541-558. 

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