Elevated brain tryptophan and enhanced 5-hydroxytryptamine turnover in acute hepatic heme deficiency: clinical implications.
Administration of 3,5-dicarbethoxy-2,6-dimethyl-4-ethyl-1,4-dihydropyridine, a suicide inhibitor of hepatic cytochrome P-450, to phenobarbital-pretreated rats rapidly causes a marked and sustained hepatic heme depletion and results in porphyria. We have shown that this event results in marked impairment of hepatic tryptophan pyrrolase activity and consequently in elevated tryptophan content and enhanced 5-hydroxytryptamine (5-HT) turnover in the brain of such porphyric rats. All these effects were reversed by administration of exogenous heme. Using an indirect assay of 5-HT-dependent function, we now show that this elevated 5-HT turnover in porphyric animals is associated with enhanced serotonergic tone. We also show that it can be potentiated by tryptophan administration, reversed by administration of exogenous heme, alleviated by treatment with p-chlorophenylalanine, an inhibitor of 5-HT synthesis, and attenuated by administration of valine, an amino acid that is known to compete with tryptophan uptake in the brain. In patients with hepatic porphyria, acute hepatic heme depletion results in severe, often life-threatening attacks. These attacks are hallmarked by neuropsychiatric symptoms of unknown etiology, but that can often be successfully treated by i.v. administration of heme. Because acute hepatic heme depletion may also be expected to compromise hepatic tryptophan metabolism in such individuals, our findings raise the possibility that elevated tryptophan content and 5-HT turnover in the brain may play a role in the neurological dysfunction associated with acute attacks of hepatic porphyria.
D000818:Animals; D001921:Brain / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D004195:Disease Models, Animal; D006418:Heme / Q000172:deficiency* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D011164:Porphyrias / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism*
D065607:Cytochrome P-450 Enzyme Inhibitors; D012701:Serotonin; D006418:Heme; D009020:Morphine; D014364:Tryptophan