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Accelerated development of uroporphyria in mice heterozygous for a deletion at the uroporphyrinogen decarboxylase locus
Author(s) -
Franklin Michael R.,
Phillips John D.,
Kushner James P.
Publication year - 2001
Publication title -
journal of biochemical and molecular toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.526
H-Index - 58
eISSN - 1099-0461
pISSN - 1095-6670
DOI - 10.1002/jbt.10000
Subject(s) - endocrinology , medicine , uroporphyrinogen iii decarboxylase , chemistry , biology , enzyme , heme , biochemistry
Three weeks after a single dose of irondextran and Aroclor 1254, mice maintained continuously on δ‐aminolevulinic acid supplemented drinking water showed significantly elevated levels of hepatic uroporphyrin and depressed (25% of normal) uroporphyrinogen decarboxylase (URO‐D) activity. Depressed URO‐D activity was paralleled by the ability of heat denatured cytosol to inhibit rhURO‐D activity. Mice heterozygous for a targeted disruption at the URO‐D locus (URO‐D +/− ) exhibited half the URO‐D activity of homozygous controls prior to treatment. After treatment, these animals showed URO‐D activity and rhURO‐D inhibitory activity comparable to similarly treated wild type (URO‐D +/+ ) mice but with significantly greater uroporphyrin accumulation. With only 10 days of treatment, URO‐D +/− but not URO‐D +/+ mice showed changes similar in magnitude to those seen after 21 days. Prior to treatment, URO‐D genotype did not influence overall hepatic P450 concentration in either sex and there was no significant difference between sexes. The treatment regimen significantly elevated P450 in animals of either URO‐D genotype and in both sexes, although the induction response at the 10‐day point was attenuated in URO‐D +/− mice. From differences in the CO absorbance maximum, and by P450 activity analysis, this attenuated induction response resulted from an attenuation of the CYP2B not the CYP1A induction. © 2001 John Wiley & Sons, Inc. J Biochem Mol Toxicol 15:287–293, 2001