This renewal application continues the main theme of research in this laboratory on the toxicology and metabolic and regulatory interactions of environmental chemicals, endocrine secretions and drugs, with heme and cytochrome P-450. The biological consequences of severe and sustained depletion of P-450 in liver and other tissues on metabolic-endocrine homeostasis will be examined in detail since agents such as the organotins exert prolonged suppressive effects on this hemeprotein and endocrine aberrations are common sequelae to toxic environmental chemical exposures. Studies of heme oxygenase are continued and this key enzyme in heme catabolism will be purified from rat liver, immunoquantitated, immunohistologically characterized and its structural homologies among several species, including man, defined. The enzyme is highly responsive to the inducing actions of diverse environmental chemicals and such induction is often associated with pronounced declines in P-450 and its related functions. New efforts will be initiated to explore basic aspects of heme metabolism in the brain and in the gastrointestinal tract. The gut is the major route by which humans are exposed to environmental chemicals; its adaptations to direct exposure to such agents are thus essential to define. The brain, protected against many, though not all, environmental agents by the blood-brain barrier, nevertheless receives the impact of such agents when the barrier is breached as by developmental state - i.e. pre- and postnatal life, by disease, or by exposure to certain environmental pollutants - i.e. metals. It is, therefore, important to characterize the biochemical responses which the brain is capable of mounting in such circumstances. The interactions of metals in producing or preventing deleterious tissue reactions are singularly revealed in the metal effects on heme synthesis, heme degradation and P-450 which we have previously defined; studies of trace metal metabolism are, therefore, directed toward further exploration of these important toxicological relationships. Finally, we propose to undertake the first isolation of a mammalian gene for a heme pathway enzyme - ALAS. This rate-limiting enzyme in heme synthesis is a major target of drugs and foreign chemicals in liver; study of its responses to such agents at a molecular level is, therefore, vital to our understanding of how environmental chemicals exert their actions at this key point in the heme-P-450 systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES001055-14
Application #
3249467
Study Section
Toxicology Study Section (TOX)
Project Start
1974-06-01
Project End
1990-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
14
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Type
Graduate Schools
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Rosenberg, D W; Kappas, A (1995) The comparative abilities of inorganic cobalt and cobalt-protoporphyrin to affect copper metabolism and elevate plasma ceruloplasmin. Pharmacology 50:201-8
Rosenberg, D W; Leff, T (1993) Regulation of cytochrome P450 in cultured human colonic cells. Arch Biochem Biophys 300:186-92
Rosenberg, D W (1993) Pharmacokinetics of cobalt chloride and cobalt-protoporphyrin. Drug Metab Dispos 21:846-9
Galbraith, R A; Drummond, G S; Kappas, A (1992) Suppression of bilirubin production in the Crigler-Najjar type I syndrome: studies with the heme oxygenase inhibitor tin-mesoporphyrin. Pediatrics 89:175-82
Mitani, K; Fujita, H; Kappas, A et al. (1992) Heme oxygenase is a positive acute-phase reactant in human Hep3B hepatoma cells. Blood 79:1255-9
Galbraith, R A; Chua Jr, S C; Kappas, A (1992) Hypothalamic mechanism for cobalt protoporphyrin-induced hypophagia and weight loss: inhibition of the feeding response to NPY. Brain Res Mol Brain Res 15:298-302
Galbraith, R A; Kow, L M; Pfaff, D et al. (1992) Injection of cobalt protoporphyrin into the medial nuclei of the hypothalamus elicits weight loss. Am J Physiol 263:R805-12
Drummond, G S; Rosenberg, D W; Kappas, A (1992) Intestinal heme oxygenase inhibition and increased biliary iron excretion by metalloporphyrins. Gastroenterology 102:1170-5
Fischbein, A; Wallace, J; Sassa, S et al. (1992) Lead poisoning from art restoration and pottery work: unusual exposure source and household risk. J Environ Pathol Toxicol Oncol 11:7-11
Rosenberg, D W (1991) Dietary modulation of cytochrome P450 in the small intestinal epithelium. Pharmacology 43:36-46

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