N. Gorman et al., Role of small differences in CYP1A2 in the development of uroporphyria produced by iron and 5-aminolevulinate in C57BL/6 and SWR strains of mice, BIOCH PHARM, 58(2), 1999, pp. 375-382
Previous work has implicated CYP1A2 in experimental uroporphyria caused by
polyhalogenated aromatic compounds, and in uroporphyria caused by iron and
5-aminolevulinate (ALA) in the absence of inducers of CYP1A2. Here we exami
ned whether the different susceptibilities of SWR and C57BL/6 strains of mi
ce to uroporphyria in the absence of inducers of CYP1A2 are related to diff
erent levels of CYP1A2. Enzymological assays (ethoxy and methoxyresorufin d
ealkylases, and uroporphyrinogen oxidation) and immunoblots indicated that
there was about twice the amount of hepatic CYP1A2 in SWR mice compared wit
h C57BL/6 mice. Immunohistochemistry revealed that CYP1A2 was located centr
ilobularly in the liver, and the staining was more intense in SWR mice than
in C57BL/6 mice. Hepatic non heme iron was about double in SWR compared wi
th C57BL/6 mice. In SWR mice given iran dextran, hepatic iron was 1.7-fold
that of C57BL/6 mice given iron dextran. SWR mice administered ALA in the d
rinking water accumulated much less hepatic protoporphyrin than did C57BL/6
mice. To confirm the importance of small increases in CYP1A2, C57BL/6 mice
were given a low dose of 3-methylcholanthrene (MC) (15 mg/kg), as well as
iron and ALA. There was about a 5- to 6- fold increase in hepatic uroporphy
rin accumulation after 32 days on ALA compared with animals not given MC. I
n these animals, CYP1A2 was increased by 10-fold at 2 days, but returned to
basal levels by 14 days. We conclude that small and transient differences
in CYP1A2 may be important in the development of uroporphyria. (C) 1999 Els
evier Science Inc.