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Biochemistry and Biophysics |
Departments of Biochemistry [I. H. H., F. P. G.] and Pathology[S. D., N. R., F. F. P.], Vanderbilt University Medical Center, Nashville, Tennessee 37232
Activation of 17ß-estradiol (E2) through the formation of catechol
estrogen metabolites, 2-OH-E2 and 4-OH-E2, and the C-16
hydroxylation product, 16-OH-E2, has been postulated to be a factor
in mammary carcinogenesis. Cytochrome P450 1B1 (CYP1B1) exceeds other
P450 enzymes in both estrogen hydroxylation activity and expression
level in breast tissue. To determine whether inherited variants of
CYP1B1 differ from wild-type CYP1B1 in estrogen hydroxylase activity,
we expressed recombinant wild-type and five polymorphic variants of
CYP1B1: variant 1 (codon 48Arg
Gly), variant 2 (codon 119AlaSer),
variant 3 (codon 432ValLeu), variant 4 (codon453Asn Ser), variant
5 (48Gly, 119Ser, 432Leu, 453Ser). The His-tagged proteins were
purified by nickel-nitrilotriacetic acid (Ni-NTA) chromatography
and analyzed by electrophoresis and spectrophotometry. We performed
assays of E2 hydroxylation activity and quantitated production of
2-OH-E2, 4-OH-E2, and 16-OH-E2 by gas chromatography/mass
spectrometry. Wild-type CYP1B1 formed 4-OH-E2 as main product
(Km, 40 ± 8
µM; kcat 4.4 ± 0.4, min-1;
kcat/Km, 110
mM-1min-1), followed by 2-OH-E2
(Km, 34 ± 4
µM; kcat, 1.9 ± 0.1 min-1;
kcat/Km, 55
mM-1min-1) and 16-OH-E2
(Km, 39 ± 5.7
µM; kcat, 0.30 ± 0.02 min-1;
kcat/Km, 7.6
mM-1min-1). The CYP1B1 variants
also formed 4-OH-E2 as the main product but displayed 2.4- to 3.4-fold
higher catalytic efficiencies
kcat/Km than the
wild-type enzyme, ranging from 270
mM-1min-1 for variant 4, to 370
mM-1min-1 for variant 2. The
variant enzymes also exceeded wild-type CYP1B1 with respect to 2- and
16-hydroxylation activity. Thus, inherited alterations in CYP1B1
estrogen hydroxylation activity may be associated with significant
changes in estrogen metabolism and, thereby, may possibly explain
interindividual differences in breast cancer risk associated with
estrogen-mediated carcinogenicity.
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