CYP1B1 gene in endometrial cancer.
Metabolic activation of estradiol has been shown to be a key factor in endometrial carcinogenesis. 4-hydroxy estrogens (CYP1B1 metabolites) received particular attention because of their causative role in malignant transformation of various organs including endometrium. CYP1B1 displays the highest level of expression in endometrium. 4-hydroxy estrogens can bind to DNA via their quinone metabolites and cause oxidative damage in endometrial cancer. Moreover, the 4-hydroxy estrogens bind to the estrogen receptor and have estrogenic effects on target tissues. Six polymorphisms of the CYP1B1 gene have been described of which four result in amino acid substitutions; 1-13C-->T, codon 48C-->G, codon 119G-->T, codon 432C-->G, codon 449T-->C and codon 453A-->G. The polymorphisms on exons 2 and 3 have significant effects on the catalytic function of CYP1B1. Polymorphisms on specific regions of CYP1B1 gene result in hyperactivation of the protein and can lead to a higher susceptibility in the incidence of various cancers. Thus, inherited alterations in CYP1B1 hydroxylation activity may be associated with significant changes in estrogen metabolism and, thereby, may possibly explain inter-individual differences in endometrial cancer risk associated with estrogen-mediated carcinogenesis.
Sasaki
Masahiro
M
Department of Urology (112F), University of California-San Francisco and Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, USA. view@itsa.ucsf.edu
Kaneuchi
Masanori
M
Fujimoto
Seiichiro
S
Tanaka
Yuichiro
Y
Dahiya
Rajvir
R
D019943:Amino Acid Substitution; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D016889:Endometrial Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D008954:Models, Biological; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012307:Risk Factors
D004967:Estrogens; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1