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.
Showing the most recent 10 out of 103 publications
