CORRESPONDENCE

More About: Modification of Clinical Presentation of Prostate Tumors by a Novel Genetic Variant in CYP3A4

Timothy R. Rebbeck

Correspondence to: Timothy R. Rebbeck, Ph.D., Department of Biostatistics and Epidemiology and Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (e-mail: trebbeck{at}cceb.med.upenn.edu).

CYP3A4 is a member of the cytochrome P450 supergene family that mediates the metabolism of numerous compounds involved in human carcinogenesis, including steroid hormones such as testosterone. Recently, a variant in the 5' regulatory region of CYP3A4 (CYP3A4-V) was reported to confer higher stage prostate tumors compared with homozygous wild-type CYP3A4 (CYP3A4-W) in both Caucasians and African-Americans (1,2). To date, these associations have not been supported by data that address the functional significance of this polymorphism.

Westlind et al. (3) recently reported that CYP3A4-V had no effect on testosterone 6ß-hydroxylation (T6ßH). However, this inference was made without any formal statistical analysis. By using the raw data provided in that paper, genotype-specific mean values of T6ßH were computed. The mean T6ßH in CYP3A4-W homozygotes (n = 36) was 1660.6 pmol/mg per minute, whereas the mean T6ßH in carriers of a CYP3A4-V allele (n = 3) was 4850.0 pmol/mg per minute. This difference was highly statistically significant by analysis of variance with F1,37 = 13.85 (P = .0007) and by Kruskal-Wallis analysis of variance by ranks with {chi}21 = 5.63 (P = .02). Thus, despite the small sample size, these data support the inference that CYP3A4-V is associated with altered testosterone metabolism.

The 2.9-fold higher T6ßH activity in CYP3A4-V relative to CYP3A4-W (Table 1Go) suggests that the downstream effect of CYP3A4-V on testosterone metabolism pathways may be physiologically relevant. However, the study of CYP3A4 expression in humans is complicated by common exposure to many inducers and inhibitors of the enzyme. For example, extremely high T6ßH was observed in one CYP3A4-V carrier in the study by Westlind et al. (3) who had exposure to barbiturates, which are known CYP3A4 inducers. Furthermore, studies of nifedipine metabolism (Table 1Go) do not indicate an association of metabolic rate with CYP3A4 genotype (5,6). Thus, additional research will be required to better define the functional significance of CYP3A4-V and to clarify the mechanism that explains the epidemiologic associations of CYP3A4-V with prostate cancer.


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Table 1. Reports of the phenotypic effects of the p450 family gene variant CYP3A4-V

 
Estimates of the ethnic distribution of CYP3A4-V have also been reported recently that mirror the rates of prostate cancer in each ethnic group. CYP3A4-V frequencies were 0% in U.S. Japanese (2), U.S. Chinese (2,6), Taiwanese (7), and Japanese (5,6); 4%-9% in U.S. and Swedish Caucasians (2,3,6,7); 9%-10% in U.S. Hispanics (2,6); and 53%-55% in African-Americans (2,6,7). Westlind et al. (3) suggested that the higher allele frequency estimate of 9% in one Caucasian sample (7) was due to genotyping errors. Genotyping is unlikely because all variants (and a subset of nonvariants) in that study were confirmed by direct sequence analysis. Given that substantial variability in allele frequency is common across ethnic groups, it is more likely that the differences in the reported frequencies of CYP3A4-V are due to ethnic or geographic differences, rather than to technical problems in mutation detection. It is noteworthy that the frequencies of CYP3A4-V are highest among African-Americans, intermediate in Caucasians, and lowest in Asians, reflecting rates of prostate cancer in each of these populations. Although far from conclusive, the initial reports of T6ßH and of CYP3A4-V frequency by ethnicity support the previously reported epidemiologic associations of CYP3A4 and prostate cancer.

REFERENCES

1 Rebbeck TR, Jaffe JM, Walker AH, Wein AJ, Malkowicz SB. Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 1998;90:1225-9.[Abstract/Free Full Text]

2 Paris PL, Kupelian PA, Hall JM, Williams TL, Levin H, Klein EA, et al. Association between a CYP3A4 genetic variant and clinical presentation in African-American prostate cancer patients. Cancer Epidemiol Biomarkers Prev 1999;8:901-5.[Abstract/Free Full Text]

3 Westlind A, Lofberg L, Tindberg N, Andersson TB, Ingelman-Sundberg M. Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5'-upstream regulatory region. Biochem Biophys Res Commun 1999;259:201-5.[Medline]

4 Amirimani B, Walker AH, Weber BL, Rebbeck TR. Response to Ando et al. Re: Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4 [letter]. J Natl Cancer Inst 1999;91:1588-90.[Free Full Text]

5 Ando Y, Tateishi T, Sekido Y, Yamamoto T, Satoh T, Hasegawa Y, et al. Re: Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4 [letter]. J Natl Cancer Inst 1999;91:1587-90.[Free Full Text]

6 Ball SE, Scatina J, Kao J, Ferron GM, Fruncillo R, Mayer P, et al. Population distribution and effects on drug metabolism of a genetic variant in the 5' promoter region of CYP3A4. Clin Pharmacol Ther 1999;66:288-94.[Medline]

7 Walker AH, Jaffe JM, Gunasegaram S, Cummings SA, Huang CS, Chern HD, et al. Characterization of an allelic variant in the nifedipine-specific element of CYP3A4: ethnic distribution and implications for prostate cancer risk. Hum Mutat 1998;12:289. (Also: Hum Mutat [serial online] 1998: 191. Available from URL: http://journals.wiley.com/1059-7794/pdf/mutation/191.pdf).[Medline]


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