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Drug-Induced Abnormalities of Liver Heme Biosynthesis
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
The iron chelate of ethylenediaminetetraacetic acid (EDTA) and nitriloacetic acid were very active at promoting the hydrogen peroxide-dependent oxidation of porphyrinogen to porphyrins, and a similar role of iron was found for the NADPH-dependent oxidation of porphyrinogens by liver microsomes in vitro. In contrast, neither the iron chelate of desferrioxamine nor ferritin iron possessed prooxidant activity, but the latter could be mobilized in an active form by incubation with EDTA. Iron was also found to promote modification of the porphyrin pigment, leading to marked loss of its Soret ab-sorbance, suggesting further (or alternative) oxidation of the porphyrin(ogen) to an open-chain degradation product. Oxidation of uro’gen to uroporphyrin and to the unidentified derivative(s) lacking Soret absorbance could under certain conditions be dissociated from each other, suggesting that they may be produced by two different mechanisms. Electron transfer (and hydrogen abstraction) may be involved in the conversion of uro’gen to uroporphyrin, whereas the degradation product may result from oxidative attack by hydroxyl radicals or, alternatively, by self-catalyzed ring opening of the corresponding heme derivative. The possibility that such a degradation product might act as a targeted inhibitor of uro’gen decarboxylase was considered, to account for the inhibitor of the enzyme which has been extracted from porphyric livers (De Matteis, 1988).
Cutaneous Porphyrias
Published in Henry W. Lim, Herbert Hönigsmann, John L. M. Hawk, Photodermatology, 2007
Gillian M. Murphy, Karl E. Anderson
UROD is a dimeric enzyme that catalyzes the sequential, clockwise removal of the four carboxyl groups from the acetic acid side chains of uroporphyrinogen III (an octacarboxyl porphyrinogen) to form the four methyl groups of coproporphyrinogen III (a tetracarboxyl porphyrinogen). Substantial deficiency of this enzyme results in accumulation of uroporphyrinogen (isomers I and III), the intermediate substrates hepta-, hexa-, and pentacarboxyl porphyrinogens, and isocoproporphyrinogen. The latter is formed from pentacarboxyl porphyrinogen by coproporphyrinogen oxidase—a minor pathway that becomes accentuated when hepatic UROD is deficient. These excess porphyrinogens (reduced porphyrins) undergo nonenzymatic oxidation to the corresponding porphyrins (uro-, hepta-, hexa-, and pentacarboxyl porphyrins, and isocoproporphyrins). The excess porphyrins circulate from the liver to the skin, where sunlight exposure generates reactive oxygen species, activates the complement system, and produces lysosomal damage (13)
Consequences of an incomplete differential diagnosis
Published in James W. Albers, Stanley Berent, Neurobehavioral Toxicology: Neurological and Neuropsychological Perspectives, 2005
James W. Albers, Stanley Berent
Other forms of intoxication that are associated with increased excretion of porphyrins include alcohol, vinyl chloride, hexachlorobenzene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, benzene, and mercury (Doss, 1987). None produces a neuropathy suggestive of porphyric neuropathy and it is unclear that this purported mechanism plays a role in any peripheral involvement. These and a variety of other chemicals can suppress enzymes involved in porphyrinogen metabolism (Ellefson, 1982).
Acute intermittent porphyria: general aspects with focus on pain
Published in Current Medical Research and Opinion, 2018
John Lidemberto Cardenas, Carlos Guerrero
Acute intermittent porphyria (AIP) is the most common acute hepatic porphyria and, in the United States, has a prevalence of 5–10 per 100,000 individuals, reaching 60–100 per 100,000 in northern European countries. It is a hereditary disease, more common in women of any age after puberty and before menopause, with a peak around the third decade. It is a disease caused by the transmission of mutations of the porphobilinogen deaminase (PBGD) gene, which is inherited in an autosomal dominant manner. The gene encoding this enzyme is located on the long arm of chromosome 11, and more than 200 of these mutations have been described. This disease has been shown to be correlated with environmental or acquired factors, which commonly precipitate acute attacks, because heme concentrations decrease or the demand is higher, requiring the increased synthesis of delta-aminolevulinic acid synthetase and stimulating the production of porphyrinogen. Drugs are among the most common precipitating factors, as was first reported with the use of sulfa drugs by Stokvis in 1889. However, the recommendations for safe medication choices in these patients are based on reports of suffering an attack during their use or the measurement of porphyrins in the urine or feces3–7.