Genetic variation of iron-induced uroporphyria in mice

• Published in: Biochemical journal Vol. 291; no. 1; pp. 29 - 35
• Main Authors: SMITH, A. G, FRANCIS, J. E
• Format: Journal Article
• Language: English
• Published: Colchester Portland Press 01.04.1993
• Subjects: Aminolevulinic Acid - pharmacology; Animals; Biological and medical sciences; Classical genetics, quantitative genetics, hybrids; Drug Tolerance - genetics; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Hydrocarbons - pharmacology; Iron - administration & dosage; Iron - toxicity; Liver - metabolism; Mice; Mice, Hairless; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred Strains; Porphyrias - chemically induced; Porphyrias - genetics; Uroporphyrinogen Decarboxylase - antagonists & inhibitors; Uroporphyrinogens - metabolism; Vertebrata; Porphyria; Vertebrata; Mammalia; Enzymatic activity; Mouse; Enzyme; Rodentia; Iron; Strain specificity; Uroporphyrinogen decarboxylase
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/bj2910029

Iron overload causes inhibition of hepatic uroporphyrinogen decarboxylase (UROD) and uroporphyria in C57BL/10ScSn but not DBA/2 mice [Smith, Cabral, Carthew, Francis and Manson (1989) Int. J. Cancer 43, 492-496]. We have investigated the induction of uroporphyria in 12 inbred strains of mice 25 weeks after iron treatment (600 mg/kg) to determine if there was any correlation with the Ah locus. Under these conditions, inhibition of UROD occurred to varying degrees in Ahd mice (SWR and AKR) as well as nominally Ahb-1 (C57BL/6J, C57BL/10ScSn and C57BL/10-cc) and Ahb-2 strains (BALB/c and C3H/HeJ). Five other Ahb or Ahd strains (C57BL/Ks, A/J, CBA/J, LP and DBA/2) were unaffected. Thus there appeared to be no correlation with the Ah phenotype and this illustrated that some other variable inherited factors are involved. Comparisons between another susceptible strain, A2G, and the congenic A2G-hr/+strain (carrying the recessive hr gene) showed a modulating influence associated with the hr locus. In contrast with individual mice of inbred strains, which showed consistent responses to iron, those of the outbred MF1 strain showed a spectrum of sensitivities as might be expected for a heterogeneic stock. The rate of porphyria development was accelerated by administration of 5-aminolaevulinic acid (5-ALA) in the drinking water, but this did not overcome strain differences. Among four strains the order of susceptibility was SWR > C57BL/10ScSn > C57B1/6J > DBA/2 (the last strain was completely resistant). With degrees of iron loading greater than 600 mg of Fe/kg (1200-1800 mg of Fe/kg) C57BL/10ScSn mice (after 20 weeks) and SWR mice (after 5 weeks which included 4 weeks of 5-ALA treatment) had less inhibition of UROD and a lower uroporphyric response, showing that there was an optimum level of liver iron concentration. Studies on selected microsomal enzyme activities associated with cytochrome P-450 showed no correlation with the propensities of strains to develop porphyria. These activities included the NADPH-dependent oxidation of uroporphyrinogen I to uroporphyrin I.