Only a few agents have been unambiguously demonstrated to be promoters in experimetal animals; butylated hydroxytoluene (BHT) is one of these. BHT promotes hepatomas in rats and pulmonary adenomas in mice. Small amounts of BHT are needed for pomotion and substances from diverse chemical classes can serve as initiators. BHT is added to foods because of its useful antioxidant properties; the dietary consumption of BHT is at one of the highest levels for any synthetic additive. It is thus of practical importance to understand the mechanisms by which BHT promotes tumors, and of considerable scientific interest to expand the study of tumor promotion to include lung. Two sensitive analytical techniques, HPLC and GC/MS, will be applied to analyze the BHT metabolites produced in vivo and in vitro. The toxic and tumor promoting effects of BHT vary between inbred strains, species and organs. By comparing the metabolites produced in a variety of systems with the physiological effects of BHT in that system, we hope to clearly identify and distinguish between the toxic and tumor promoting derivatives of this compound. Protein phosphorylation regulates many biological activities and protein kinases have been directly implicated in cell transformation by tumor viruses. Tumor promotors may also disrupt normal cellular control of protein phosphorylation. The calmodulin-dependent and phospholipid-dependent Ca++-activated kinases will be characterized in the lungs of mice after urethane (initiator) and BHT (promoter) administration. Aphotoaffinity analog of cyclic GMP, 8-N3-(32P)cGMP, will be used to monitor the kinases activated by cyclic GMP. A photoaffinity analog of ATP, 8-N3-(32P)ATP will be used to monitor other kinases in whole lung extracts and in isolated populations of the Type 2 cells from which the adenomas are derived. Glucocorticoids inhibit proliferation of Type 2 cells, accelerate differentiation of these cells, and inhibit the toxic effects of BHT on mouse lung. Whether glucocorticoids affect the promoting activity of BHT will be tested. Using a new procedure for in vitro autoradiography, the effects of BHT on the cellular location of pulmonary glucocorticoid receptors will be determined.
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