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VA Medical Center; Departments of
Biochemistry and
Pharmacology/Toxicology, Dartmouth Medical School (P.R.S., N.G.,
H.S.W., J.F.S) and Departments of
Pharmacology and Medicine, Cornell
University Medical College (C.A.L., A.B.R.)
Uroporphyrinogen is an intermediate of the heme biosynthetic
pathway. The oxidation of uroporphyrinogen to uroporphyrin (UROX) has
been demonstrated to be catalyzed by mammalian CYP1A2. This reaction
has an important role in uroporphyria caused by halogenated aromatic
compounds. Two CYP enzymes induced by Ah receptor ligands were purified
recently from chick embryo liver. One, designated CYP1A5, was
preferentially active in arachidonic acid epoxygenation and the other,
designated CYP1A4, in 7-ethoxyresorufin deethylase (EROD) and aryl
hydrocarbon hydroxylase (AHH), reactions mainly catalyzed by CYP1A1 in
rodents. The amino acid sequences of both CYP1A5 and CYP1A4 are more
similar to CYP1A1 than to 1A2, and neither can be classified as an
ortholog of mammalian CYP1A1 or 1A2. Here we report that reconstituted
purified CYP1A5 was eight times more active than CYP1A4 in catalyzing
UROX. The stimulation of UROX by 3,4,3
,4-tetrachlorobiphenyl that has
been observed in microsomes was also observed with the reconstituted
enzymes. Similar dose response relationships were found for induction
of UROX and EROD in both chick embryo liver microsomes and in cultured chick hepatocytes, indicating coinduction of CYP1A5 and CYP1A4. UROX
was induced by the Ah receptor ligand, 3-methylcholanthrene, in chicken
kidney as well as liver. The findings reported here and other evidence
that CYP1A4 and CYP1A5 tend to exhibit CYP1A1 and 1A2-like enzyme
activites, respectively, indicate that the division of some enzyme
activities among CYP1A enzymes applies to different vertebrate classes.
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