Heme is the prosthetic moiety of hemoproteins involved in vital cellular functions of all aerobic organisms. As such, its metabolism is very finely regulated to meet the prevailing cellular needs of the organism. Genetic lesions in heme synthesis occur in humans, and are characteristic of the heme-deficient states, known as the porphyrias. In porphyric individuals, a variety of factors including drugs and diet frequently precipitate acute life-threatening attacks characterized by grave neuropsychiatric and abdominal symptoms. In some of these individuals, glucose therapy is beneficial, while in those who remain refractory, intravenous heme is found to dramatically relieve such symptoms. However, the mechanisms of either glucose- or heme-mediated amelioration have remained elusive and ill-understood. Unconvinced by the existing mechanistic explanations and in search of etiological clues, we have re-examined the metabolic effects of acute heme-deficient states. Such reappraisal has led to our working hypothesis that enhanced L-tryptophan, resulting from impairment of hepatic tryptophan pyrrolase in acute heme deficiency, is a common denominator of the heme-reversible biochemical abnormalities and the neuropsychiatric symptomatology of acute hepatic porphyrias. Studies are now proposed to determine whether L-tryptophan might also be the hepatoneural link to the abdominal symptoms, a cardinal feature of acute hepatic porphyrias, and to elucidate whether glucose-mediated amelioration of neurologic symptoms might be due to circumvention of a tryptophan-mediated block in gluconeogenesis. Hepatic heme is also essential for the assembly of hepatic hemoproteins cytochrome P-450s and tryptophan pyrrolase, its most avid consumers. However very little is known about the mechanics of actual assembly and whether these hemoproteins are regulated by hepatic heme availability. Studies are proposed to probe those particular aspects as well as to elucidate the structure-function relationships when cytochrome P-450(s) heme moiety is substituted by the unnatural analog mesohemin. Finally, studies are proposed to examine substrate-mediated inactivation of certain cytochrome P-450 isozymes, the contributions of such inactivation to acute hepatic heme deficiency and to impairment of tryptophan pyrrolase.
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