Hexachlorobenzene Treatment on Hepatic Mitochondrial Function Parameters and Intracellular Coproporphyrinogen Oxidase Location

Abstract

These studies try to elucidate why isocoproporphyrin appears in hexachlorobenzene-poisoned rats' feces. Chronic exposure of hexachlorobenzene to rats produces an experimental model for human porphyria cutanea tarda. After 8 weeks of treatment, rats showed high porphyrin excreta and 50% inhibition of liver uroporphyrinogen decarboxylase activity. Uroporphyrin plus heptacarboxylic porphyrin exceeded coproporphyrin in urine, whereas in feces, isocoproporphyrin, from abnormal pentacarboxylic porphyrinogen III oxidative decarboxylation by liver coproporphyrinogen oxidase, became the main porphyrin. Trypsin-treated mitochondria showed that the outer and inner membrane permeability barrier was highly conserved after hexachlorobenzene intoxication. In digitonin-treated hexachlorobenzene mitochondria, coproporphyrinogen oxidase was free in the mitochondrial intermembrane space, whereas in normal mitochondria, 30% to 50% remained anchored to the inner membrane. Hexachlorobenzene led to a decrease in respiratory control and ADP/O ratios (uncoupled mitochondria). Albumin restored oxidative phosphorylation, indicating no irreversible inner membrane damage. Normal and hexachlorobenzene mitochondria oscillatory studies exhibited similar damping factor values, showing that hexachlorobenzene had no significant effect on membrane fluidity and elasticity. Mitochondrial uncoupling could explain the free state of the enzyme within the intermembrane space. The free state of the enzyme makes it more flexible and would allow pentacarboxylic porphyrinogen III, whose levels are increased, to compete with coproporphyrinogen III and being transformed into dehydroisocoproporphyrinogen, the liver forerunner of fecal isocoproporphyrin.

Exposure to Environmental Pollutants and Their Association with Biomarkers of Aging: A Multipollutant Approach

“…Toxic manifestations of HCB exposure can include porphyria, for which the liver as well as the kidneys are the main targets. Although molecular mechanisms of toxicity responses remain to be elucidated, experimental evidence shows involvement of the mitochondria in which the induction of oxidative stress may play a role. − Some perfluorinated compounds are known to stimulate peroxisomes, which catabolise fatty acids that are then to be transported to the mitochondria for β-oxidation. Interference with mitochondrial energetics and biogenesis is shown for some peroxisome proliferators.…”

Separation and fragmentation study of isocoproporphyrin derivatives by UHPLC-ESI-exact mass MS/MS and identification of a new isocoproporphyrin sulfonic acid metabolite

“…CPOX metabolises pentacarboxylic acid porphyrinogen III into dehydroisocoproporphyrinogen by oxidative decarboxylation of the propionic acid group on the A ring into a vinyl group (Fig. ) . Dehydroisocoproporphyrinogen is oxidised and excreted in the faeces where further metabolism by intestinal flora results in isocoproporphyrin and its derivatives (Fig.…”

“…1). [14] Dehydroisocoproporphyrinogen is oxidised and excreted in the faeces where further metabolism by intestinal flora results in isocoproporphyrin and its derivatives ( Fig. 1) Figure 2 shows UHPLC-ESI-MS extracted ion chromatograms of the [M + H] + ions of isocoproporphyrin derivatives extracted from the faeces of rats exposed to HCB.…”

Erythroid Heme Biosynthesis and Its Disorders

“…Even so, current dogma relegates pathway regulation in all cells to ALAS-1 or -2 with the proposition that all later pathway enzymes are present in excess. This model conveniently ignores the observation that coproporphyrin is routinely excreted by mammals (Kappas et al 1995), and that in cancer cells one finds an elevation of CPOX and diminishment of FECH that results in the accumulation of protoporphyrin during ALA-based phototherapy (Sopena et al 2008;Takahashi et al 2011). Additional recent data may cause a reevaluation of this model for differentiating erythroid cells since it has been discovered that a mutation in the carboxyl terminus of ALAS-2, which results in a hyperactive enzyme, results in vivo in the accumulation of free protoporphyrin and zincbound protoporphyrin (Whatley et al 2008).…”