Relative roles of CYP2E1 and CYP1A2 in mouse uroporphyria caused by acetone.
Porphyria cutanea tarda is a liver disease characterized by excess production of uroporphyrin. We previously reported that acetone, an inducer of CYP2E1, enhances hepatic uroporphyrin accumulation in mice treated with iron dextran (Fe) and 5-aminolevulinic acid (ALA). Cyp2e1(-/-) mice treated with Fe and ALA were used to investigate whether CYP2E1 is required for the acetone effect. Hepatic uroporphyrin accumulation was stimulated by acetone in Cyp2e1(-/-) mice to the same extent as in wild-type mice. In the absence of acetone, uroporphyrin accumulated in Cyp2e1(-/-) mice treated with Fe and ALA, but less than in wildtype mice. However, in Cypla2(-/-) mice, uroporphyrin accumulation caused by Fe and ALA, with or without acetone, was completely prevented. Acetone was not an inducer of hepatic CYP1A2 in the wild-type mice. Although acetone is an inducer of CYP2E1, CYP1A2 appears to have the essential role in acetone-enhancement of uroporphyria.
Sinclair
P R
PR
VA Medical Center, White River Junction, Vermont 05009, USA. psinc@dartmouth.edu
Gorman
N
N
Walton
H S
HS
Bement
W J
WJ
Szakacs
J
J
Gonzalez
F J
FJ
Dalton
T P
TP
Nebert
D W
DW
Sinclair
J F
JF
D000096:Acetone / Q000494:pharmacology*; D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000502:physiology*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007501:Iron / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism; D017119:Porphyria Cutanea Tarda / Q000201:enzymology; D014577:Uroporphyrinogens / Q000378:metabolism; D014578:Uroporphyrins / Q000096:biosynthesis*
D014577:Uroporphyrinogens; D014578:Uroporphyrins; D000096:Acetone; D000622:Aminolevulinic Acid; D003577:Cytochrome P-450 Enzyme System; D007501:Iron; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2