Increased delta aminolevulinic acid and decreased pineal melatonin production. A common event in acute porphyria studies in the rat.

Abstract

Tryptophan (TRP) is the precursor of melatonin, the primary secretory product of the pineal gland. Hepatic heme deficiency decreases the activity of liver tryptophan pyrrolase, leading to increased plasma TRP and serotonin. As a paradox, patients with attacks of acute intermittent porphyria (AIP), exhibit low nocturnal plasma melatonin levels. This study using a rat experimental model was designed to produce a pattern of TRP and melatonin production similar to that in AIP patients.Pineal melatonin production was measured in response to: ( a ) a heme synthesis inhibitor, succinylacetone, ( b ) a heme precursor, ␦ -aminolevulinic acid (Ala), ( c ) a structural analogue of Ala, ␥ -aminobutyric acid. Studies were performed in intact rats, perifused pineal glands, and pinealocyte cultures. Ala, succinylacetone, and ␥ -aminobutyric acid significantly decreased plasma melatonin levels independently of blood TRP concentration. In the pineal gland, the key enzyme activities of melatonin synthesis were unchanged for hydroxyindole-O-methyltransferase and decreased for N -acetyltransferase.Our results strongly suggest that Ala overproduced by the liver acts by mimicking the effects of ␥ -aminobutyric acid on pineal melatonin production. These data could account for the low plasma melatonin in AIP. They also support the view that Ala acts as a toxic element in the pathophysiology of AIP. ( J. Clin. Invest. 1996. 97:104-110.) Key words: porphyria • melatonin • ␦ -aminolevulinic acid • tryptophan • ␥ -aminobutyric acid

Melatonin Synthesis in the Rat Harderian Gland: Age- and Time-related Effects

“…The rodent Harderian gland contains considerable amounts of porphyrins (Spike et al, 1992) known to cause a toxic light-mediated effect due to their capability to generate free radicals. A relationship between porphyrins and melatonin have been reported in a rat model of acute porphyria (Puy et al, 1996) and in patients with reiterated acute intermittent porphyria attacks (Puy et al, 1993). Melatonin has been shown to be a potent free radical scavenger (Reiter et al, 1999).…”

Inhibition of 5‐aminolevulinic acid‐induced DNA damage by melatonin, N1‐acetyl‐N2‐formyl‐5‐methoxykynuramine, quercetin or resveratrol

“…In AIP patients a reduction in the plasma concentration of melatonin during the acute attacks has been observed [49] and a reduced production of melatonin was observed in chronically ALA‐treated rats [50]. Pretreatment with melatonin caused an increase in the PBGD and ALA dehydratase in the brain of ALA‐treated rats, suggesting an antioxidant effect of melatonin in heme biosynthesis [51].…”

Modern diagnosis and management of the porphyrias

“…While the exact mechanism underlying these complaints is not yet well understood, various hypotheses have been put forward. For example, (i) excess amounts of PBG or ALA may cause neurotoxicity (Meyer et al , 1998); (ii) increased ALA concentrations in the brain may inhibit gamma‐aminobutyric acid release (Mueller & Snyder, 1977; Brennan & Cantrill, 1979); (iii) haem deficiency may result in degenerative changes in the central nervous system (Whetsell et al , 1984); (iv) decreased haem synthesis in the liver results in decreased activity of hepatic tryptophan pyrrolase (TP), a haem‐dependent enzyme, possibly resulting in increased levels of brain tryptophan and increased turnover of 5‐hydroxytryptamine, a neurotransmitter (Litman & Correia, 1985); (v) as all of the porphyrias that are associated with neurovisceral complaints show increased urinary excretion of ALA (ADP), or of ALA and PBG [AIP, hereditary coproporphyria (HCP) and variegate porphyria (VP)], and ALA increases lipid peroxidation, ALA‐mediated lipid peroxidation may underscore the acute crisis of porphyria (Bechara, 1996); and (vi) TP deficiency results in decreased plasma melatonin levels (Puy et al , 1996), which may result in the loss of protection against ALA‐mediated lipid peroxidation.…”