Human CYP1B1 Leu432Val gene polymorphism: ethnic distribution in African-Americans, Caucasians and Chinese; oestradiol hydroxylase activity; and distribution in prostate cancer cases and controls

Abstract

Cytochrome P4501B1 (CYP1B1) is involved in the activation of many carcinogens and in the metabolism of steroid hormones, including 17beta-oestradiol (E2) and testosterone. We report a significant difference in the allele frequencies of two point mutations in the coding region of the CYP1B1 gene among Caucasian (n = 189), African-American (n = 52) and Chinese (Linxian) (n = 109) populations. A (C to G) transversion at position 1666 in exon 3, which results in an amino acid substitution of Leu432 to Val, was present in African-Americans with an allele frequency for Va1432 of 0.75, in Caucasians of 0.43, and in Chinese of 0.17. A (C to T) transition at position 1719 in exon 3, with no amino acid change (Asp449), appeared to be closely linked with the Val432 variant. Results using human lung microsomal preparations from individuals with the CYP1B1Val/Val and CYP1B1Leu/Leu genotypes indicate that Val432 variant may be a high activity allele and thus may contribute to the interindividual differences in CYP1B1 activity. Because CYP1B1 is involved in hormone and carcinogen metabolism, and given the disparate rates of prostate cancer among ethnic groups, we also evaluated the association of the CYP1B1 Leu432Val polymorphism with prostate cancer risk in a pilot case-control study. Among Caucasians, 34% of men with cancer (n = 50) were homozygous for the Val432 polymorphism, while only 12% of matched control subjects (n = 50) had this genotype. These preliminary data indicate that genetic polymorphisms in CYP1B1 might play an important role in human prostate carcinogenesis.

Pharmacogenetics and Regulation of Human CytochromeP450 1B1: Implications in Hormone-Mediated Tumor Metabolism and a Novel Target for Therapeutic Intervention

“…Whereas the 432V/V allele was responsible for increased prostate cancer risk, the 432V/V and 432V/L polymorphisms further increased risk associated with an Alu repeat in exon 7 of the progesterone receptor, suggesting a possible role of CYP1B1 in progesterone receptor pathways (58). The CYP1B1*3 allele was also associated with increased cancer incidence in a Caucasian population; however, this study suffered from a very low sample size (154). Another report found that the A119S was associated with increased cancer risk in Japanese prostate cancer cases, whereas other alleles (CYP1B1*1, CYP1B1*3, and CYP1B1*4) were not associated (16).…”

“…Estrogen exposure has been implicated in the disease etiology of prostate cancer (152), and CYP1B1 has been implicated as an important gene up-regulated in prostate cancer (153). Those alleles associated with alterations in promoter or protein function may be responsible for modulating the metabolic effects of CYP1B1 in tumor tissue (16,58,112,154). CYP1B1 is frequently found in prostate carcinomas but usually at either weak or moderate staining intensity (see Table 1; ref.…”

“…The 48G/G, 432V/V, and A119S/S CYP1B1 polymorphisms were found to be associated with increased cancer risk alone or in combination with other factors (16,58,112,154). Whereas the 432V/V allele was responsible for increased prostate cancer risk, the 432V/V and 432V/L polymorphisms further increased risk associated with an Alu repeat in exon 7 of the progesterone receptor, suggesting a possible role of CYP1B1 in progesterone receptor pathways (58).…”

Genetic polymorphisms, hormone levels, and hot flashes in midlife women

“…One band at 271 bp, one band at 166 bp, and one band at 105 bp indicated heterozygosity (+/−). Bands located at 166 bp and 105 bp indicated homozygosity for the mutant allele (−/−) [5,[25][26][27]. Detection of the CYP1A1 polymorphism was carried out using published methods and primers used were: forward 5′-CAGTGAAGAGGTGTAGCCGCT-3′, reverse 5′-TAGGAGTCTTGTCTCATGCCT-3′.…”

Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer

“…14 The CYP1B1*3 polymorphism has been associated with increased CYP1B1 mRNA expression, 15 increased catalytic activity [16][17][18] and specifically altered estrogen hydroxylation activity with the potential to interfere with tumor biology. 17,[19][20][21] Overexpression of the adenosine triphosphate-binding cassette transporters ABCB1 and ABCG2 has been associated with resistance to taxane-based agents in vitro, 22 although there is minimal evidence to suggest a role for paclitaxel as a substrate for ABCG2. ABCB1 appears to be the main paclitaxel transporter 23,24 and variants in ABCB1 have been demonstrated to alter P-glycoprotein expression.…”