© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 8, 630,
April 17, 2002
© 2002 Oxford University Press
CORRESPONDENCE |
Re: Modification of Clinical Presentation of Prostate Tumors by a Novel Genetic Variant in CYP3A4
Affiliations of authors: L. Wojnowski, E. Hustert, M. Haberl, I. Koch, J. Klattig, Epidauros Biotechnologie AG; K. Klein, U. Zanger, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; J. Kirchheiner, Institute of Clinical Pharmacology, University Medical Center Charite, Humboldt University, Berlin, Germany.
Correspondence to: Epidauros Biotechnologie AG, D-82347 Bernried, Germany (e-mail: info{at}epidauros.com).
The variable expression and activity of CYP3A isozymes observed in the population has been discussed as a factor that affects both response to therapies and the individual cancer predisposition. The CYP3A4-V gene variant in the 5`-regulatory region of the CYP3A4 gene (herein referred to as CYP3A4*1B) was associated with high-grade prostate cancer (1) and with a reduced risk for treatment-related leukemia (2). It has been postulated that CYP3A4*1B might reduce CYP3A4 expression and thereby decrease both steroid metabolism in the prostate and production of DNA-damaging chemotherapeutic metabolites (1,2). However, although the single nucleotide polymorphism disrupts a putative regulatory element in the CYP3A4 promoter, several studies did not detect any substantial effect of CYP3A4*1B on CYP3A4 expression or activity [(3) and references therein].
We noticed a tight linkage between CYP3A4*1B and CYP3A5*1A, a recently described marker of the CYP3A5 polymorphism (4,5). In 230 DNA samples isolated from Caucasians with a variety of medical conditions, the allelic frequencies of CYP3A4*1B and CYP3A5*1A were 3.7% (95% confidence interval [CI] = 2% to 5.4%) and 5.4% (95% CI = 3.3% to 7.5%), respectively. Three of 230 individuals were heterozygous for the CYP3A4*1B allele, 12 individuals were heterozygous for the CYP3A5*1A allele, and 12 individuals were heterozygous for both alleles. One individual was homozygous for CYP3A4*1B and heterozygous for CYP3A5*1A. This distribution was statistically significantly different (P<.001, Fisher's exact test) from that expected for independently recombining alleles and indicated that, despite a physical distance of approximately 110 kb (6), CYP3A5*1A and CYP3A4*1B constitute a haplotype in double-heterozygous individuals.
These frequencies and their distribution predicted that approximately 80% of carriers of CYP3A4*1B alleles would exhibit increased CYP3A5 messenger RNA (mRNA) expression. In agreement with this prediction, CYP3A5 mRNA expression was increased in four of five available liver samples that were heterozygous for CYP3A4*1B alleles (Fig. 1
, upper panel). The increase in CYP3A5 expression was restricted to samples that were simultaneously heterozygous for the CYP3A5*1A allele. By contrast, the presence of CYP3A4*1B alleles alone was not necessary for the increased CYP3A5 expression. These data show that CYP3A5 expression is increased in individuals carrying CYP3A4*1B alleles if they are simultaneously carriers of CYP3A5*1A alleles.
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In conclusion, in approximately 80% of Caucasians carrying CYP3A4*1B, this allele is associated with increased CYP3A5 expression because of its linkage with CYP3A5*1A. The reported association between the CYP3A4*1B allele and high-grade prostate cancer (1) may, therefore, be caused by increased CYP3A5 expression rather than by altered expression or activity of CYP3A4. This hypothesis is strongly supported by the observation that, unlike its expression in the liver and the intestine, CYP3A5 but not CYP3A4 is expressed in the prostate (Fig. 1
, lower panel). The reported association between CYP3A4*1B and a reduced risk of treatment-related leukemia (2) could be caused by CYP3A5-specific metabolic reactions. CYP3A proteins participate in the metabolism of most chemotherapeutic drugs currently in use. Reactions catalyzed exclusively by CYP3A5 have been reported for several substances, including the cancer drug irinotecan and the liver carcinogen aflatoxin B1 (7). Together, our observations provide an explanation for the association between prostate cancer and CYP3A4*1B expression. In addition, they suggest that differences between catalytic activities of CYP3A4 and CYP3A5 should be investigated in a systematic manner.
NOTES
Present address: Leszek Wojnowski, M.D., Dept. of Clinical Pharmacology, Georg-August-University Goettingen, Federal Republic of Germany (e-mail: Leszek.Wojnowski{at}med.uni-goettingen.de).
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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 [published erratum appears in J Natl Cancer Inst 1999;91:1082]. J Natl Cancer Inst 1998;90:1225–9.
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Felix CA, Walker AH, Lange BJ, Williams TM, Winick NJ, Cheung NK, et al. Association of CYP3A4 genotype with treatment-related leukemia. Proc Natl Acad Sci U S A 1998;95:13176–81.
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Rebbeck TR. More about: modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4 [letter]. J Natl Cancer Inst 2000;92:76.
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5 Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001;27:383–91.[CrossRef][Web of Science][Medline]
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