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 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 1) 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 1
) 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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REFERENCES
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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.
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.
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]
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Amirimani B, Walker AH, Weber BL, Rebbeck TR. Response to
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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.
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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