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Vol. 61, Issue 3, 586-594, March 2002
Division of Molecular Toxicology, Institute of Environmental
Medicine, Karolinska Institutet, Stockholm, Sweden (E.A., M.O., M.H.,
M.I.-S.); and AstraZeneca Mölndal R&D, Molecular Biology,
Mölndal, Sweden (B.T., C.O.)
Cytochrome P450 1B1 (CYP1B1) is an extrahepatic enzyme of
potential importance for the metabolism of estrogen and for metabolic activation of environmental carcinogens. We investigated an Ethiopian population for functional polymorphisms in the CYP1B1
gene using genomic DNA sequencing and detected three novel single
nucleotide polymorphisms (SNPs). One of these (4360C
G in exon 3) is
present at a frequency of 7% and causes an Ala443Gly amino acid
substitution. In addition, the four described previously missense
mutations Arg48Gly, Ala119Ser, Leu432Val, and Asn453Ser were found with frequencies of 51, 50, 53, and 2%, respectively, yielding a total of
32 possible CYP1B1 haplotypes. Allele-specific PCR
methods for haplotype analysis were developed and seven different
CYP1B1 alleles were found: CYP1B1*1, *2, *3, *4,
*5, *6, and *7 with frequencies of 8, 37, 39, 2, 0.7, 6, and 7%, respectively. The functional properties of different
forms of CYP1B1, as well as of the Leu432Val + Asn453Ser and Leu432Val + Ala443Gly variants, were evaluated after heterologous expression of
the corresponding cDNAs in Saccaromyces cerevisiae. The
results revealed that CYP1B1.6 and CYP1B1.7, having the amino acid
substitutions Arg48Gly, Ala119Ser, and Leu432Val in common, exhibited
altered kinetics with significantly increased apparent
Km and lowered
Vmax values for both the 2- and
4-hydroxylation of 17 
-estradiol, whereas the other constructs were
indistinguishable from the CYP1B1.1 enzyme. The results emphasize the
necessity of a complete haplotype analysis of enzyme variants for
evaluation of functional consequences in vivo and for analyses of
genetic polymorphisms in relation to, for example, cancer incidence.
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