Investigation of genes involved in an iron and chemically-induced malfunction of haem biosynthesis.

Porphyria cutanea tarda (PCT) belongs to a group of diseases that result from malfunctions of the haem biosynthetic pathway. PCT is caused by a reduction in the activity of the enzyme uroporphyrinogen decarboxylase (UROD) which can be inherited as a mutation in the UROD gene or acquired through moderate liver damage. This sporadic type of PCT is commonly associated with exposure to alcohol, oestrogens, iron or polyhalogenated chemicals. Although the mechanism underlying the sporadic condition is still under speculation, a variation in the response to these agents has suggested a genetic predisposition, unrelated to a mutation in UROD, is required. An experimental porphyria that develops in mice treated with hexachlorobenzene and iron has been studied because of its analogy with sporadic PCT. The severity of this porphyria is dependent on the strain of mouse used, again indicating a genetic susceptibility. To study the genetic element of the experimental condition, F2 intercrosses were bred from the most susceptible and most resistant strains and a basic microsatellite linkage analysis was undertaken. This analysis has revealed three chromosomes: 12, 14 and 17, that correlated with susceptibility to porphyria. One proposed candidate for the susceptibility locus chromosome 12 was the Ahr gene, which encodes the aromatic hydrocarbon receptor, was investigated further by restriction fragment length polymorphism analysis. No correlation with the mouse Urod gene, either by linkage or expression analysis, was discovered, hence a mutation or polymorphism in this gene does not appear to explain the reduction in activity of this enzyme in the experimental condition. Two further genes cyp1a1 and cyp1a2 (encoding the cytochrome P450 isozymes 1A1 and 1A2) under regulational control of the Ahr gene were also examined extensively. Again no significant linkage was detected, more over, there appeared to be no significant correlation with expression or activity of either isozyme and susceptibility to the experimental condition.