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.
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 examined whether the different susceptibilities of SWR and C57BL/6 strains of mice to uroporphyria in the absence of inducers of CYP1A2 are related to different levels of CYP1A2. Enzymological assays (ethoxy- and methoxyresorufin dealkylases, and uroporphyrinogen oxidation) and immunoblots indicated that there was about twice the amount of hepatic CYP1A2 in SWR mice compared with C57BL/6 mice. Immunohistochemistry revealed that CYP1A2 was located centrilobularly 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 with C57BL/6 mice. In SWR mice given iron dextran, hepatic iron was 1.7-fold that of C57BL/6 mice given iron dextran. SWR mice administered ALA in the drinking 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 uroporphyrin accumulation after 32 days on ALA compared with animals not given MC. In 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.
Gorman
N
N
Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA.
Walton
H S
HS
Bement
W J
WJ
Honsinger
C P
CP
Szakacs
J G
JG
Sinclair
J F
JF
Sinclair
P R
PR
D000622:Aminolevulinic Acid / Q000494:pharmacology*; D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000032:analysis / Q000378:metabolism*; D007150:Immunohistochemistry; D007501:Iron / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D013045:Species Specificity; D014578:Uroporphyrins / Q000378:metabolism / Q000652:urine*
D014578:Uroporphyrins; D000622:Aminolevulinic Acid; D007501:Iron; D019388:Cytochrome P-450 CYP1A2