Genetic traits and diet triggering the iron-induced hepatic model of the idiopathic disorder sporadic porphyria cutanea tarda

Metabolic disorders can be the consequence of external factors and individual susceptibility. Sporadic porphyria cutanea tarda (sPCT) is an idiopathic disorder of liver heme synthesis exhibiting inhibition of uroporphyrinogen decarboxylase, characterised by dermal and hepatic deposition of uroporphyrins from oxidation of sensitive uroporphyrinogens (uroporphyria). sPCT is associated with alcohol, estrogenic drugs, HIV and hepatitis C, as well as a poorly understood influence of iron. Hexachlorobenzene (HCB) and reputably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cause a similar disorder. The hepatic aspects modelled in susceptible rodents in response to HCB and TCDD are potentiated by iron. Importantly, iron overload alone eventually causes hepatic uroporphyria in genetically susceptible mice. To determine whether this genetic susceptibility to iron toxicity is the consequence of a single genetic variant or is multigenic, a low power F2 intercross cross from sensitive SWR and resistant DBA/2 strains was used to detect chromosomal quantitative trait loci (QTL) associated with uroporphyria development enhanced by the heme precursor 5-aminolevulinic acid (5-ALA). Multiple QTL contributed to the development of uroporphyria. Differential gene expressions comparing mice of parent strains and the F2 extremes of resistance and susceptibility suggested possible contributions associated with QTL. Positions of QTL and the confidence regions were compared with those observed previously for uroporphyria induced more rapidly by TCDD in iron-loaded mice and showed overlapping but not identical loci. A difference in uroporphyric response to iron loading occurred with another sensitive strain, C57BL/10ScSn, whether maintained on one of two well-defined, but similar, same source commercial diets. Uroporphyria developed with a nutritionally enhanced diet rather than a lean maintenance diet. One common observation with uroporphyria was decreased expression of Glul for glutamine synthetase. The findings illustrate the interaction of polygenic factors, external factors and diet in models of idiopathic human disorders such as sPCT.