A thorough understanding of both the mechanism and the clinical application of drug metabolism in the context of pharmacogenetics provides the clinician with the greatest opportunity for identifying and determining the relevancy of a particular interaction or adverse drug event. The table below is a summary of the main genetic polymorphisms (or variations) of cytochrome P450 (CYP) 3A4 and if known, the populations primarily affected, the specific genetic mutation, and the impact of that mutation on enzyme activity.1-14  Compared to other CYP enzymes involved in drug metabolism, it is well known that a large portion of medications dependent on phase I metabolic pathways, will rely upon or be substrates of CYP3A4.16  Medications substrates which are dependent on the presence and/or functional activity of CYP3A4 may not be metabolized as efficiently in the presence of one of these known genetic polymorphisms.  As such, these patients may experience exaggerated or unexpected pharmacologic and/or side effects due to the higher concentrations of the medication substrate present in the body.   

The important points to take away from this publication include the following: 1) The majority of genetic polymorphisms to the CYP3A4 gene result in decreased function and a few having no influence on enzyme activity; 2) With the exception of the genetic polymorphism CYP3A4*1B, CYP3A4*10 in Hispanics, and CYP3A4*19 in Indo-Pakistanis, the proportion of patients without a genetic polymorphism appears low; and 3) While some ethnicities are represented, there are still a large number of patient populations where the impact of these genetic polymorphisms have not been fully evaluated.

As a brief review, the genetic variations can be interpreted by the location and/or type of mutation or defect in the genetic code or sequence.  For example, patients with the genetic polymorphism CYP3A4*2 are known to have a single nucleotide polymorphism at position 15,713 in the nucleotide sequence within exon 7 for the gene that encodes for CYP3A4 enzyme.  The nucleotide, thymine at position 15,713 is changed to another nucleotide, cytosine.  This single change in the nucleotide changes the codon (3 nucleotide sequence) for the type of amino acid placed at position 222 in the amino acid chain (once the gene transcript has been translated by the ribosomes).  Therefore, instead of a serine (S; Ser) being placed at position 222 the amino acid, proline (P; Pro) has replaced its position.  This type of genetic variation is called a missense mutation.

While there is still a need for clinical research on the impact of genetic polymorphisms on drug efficacy and safety, we do know that some of these variations have been associated with changes in drug metabolism and/or elimination.  For a list of medication substrates that have the potential to be impacted by some of these genetic polymorphisms, we recommend you go to the Drug Tables available online.

References:

1. Gonzalez FJ, Schmid BJ, Umeno M et al. Human P450PCN1: sequence, chromosome localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase.  DNA 1988;7:79-86.
2. Rebbeck TR, Jaffe JM, Walker AH et al. Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4.  J Natl Cancer Inst  1998;19:1225-9.
3. Walker AH, Jaffe JM, Gunasegaram S et al. Characterization of an allelic variant in the nifedipine-specific element of CYP3A4: ethnic distribution and implications for prostate cancer risk. Mutations in brief no. 191.  Hum Mutat 1998;12:289.  
4. Sata F, Sapone A, Elizondo G et al. CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity.  Clin Pharmacol Ther  2000;67:48-56.  
5. Cavaco I, Gil JP, Gil-Berglund E et al.  CYP3A4 and MDR1 alleles in a Portuguese population.  Clin Chem Lab Med 2003;41:1345-50.  
6. Sata F, Sapone A, Elizondo G et al. CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity.  Clin Pharmacol Ther 2000;67:48-56.  
7. Hsieh KP, Lin YY, Cheng CL et al.  Novel mutations of CYP3A4 in Chinese.  Drug Metab Dispos  2001;29:268-73.  
8. Van Schaik RH, de Wildt SN, Brosens R et al.  The CYP3A4*3 allele: is it really rare?  Clin Chem 2001;47:1104-6.  
9. Eiselt R, Domanski TL, Zibat A et al. Identification and functional characterization of eight CYP3A4 protein variants.  Pharmacogenetics 2001;11:447-58.  
10. Lamba JK, Lin YS, Thummel K et al. Common allelic variants of cytochrome P4503A4 and their prevalence in different populations.  Pharmacogenetics  2002;12:121-32.  
11. Dai D, Tang J, Rose R et al. Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos.  J Pharmcol Exp Ther  2001;299:825-31.  
12. Fukushima-Uesaka H, Saito Y, Watanabe H et al. Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population.  Human Mutat 2004;23:100.  
13. Lee SJ, Bell DA, Coulter SJ et al. Recombinant CYP3A4*17 is defective in metabolizing the hypertensive drug nifedipine, and the CYP3A4*17 allele may occur on the same chromosome as CYP3A5*3, representing a new putative defective CYP3A haplotype.  J Pharmacol Exp Ther 2005;313:302-9. 
14. Westlind-Johnsson A, Hermann R, Huennemeyer A et al. Identification and characterization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity.  Clin Pharmacol Ther 2006;79:339-49.  
15. Zhou Q, Yu X, Shu C et al.  Analysis of CYP3A4 genetic polymorphisms in Han Chinese.  J Hum Genet 2011;[Epub ahead of print].  
16. Rendic S, Ci Carlo FJ.  Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors.   Drug Metab Rev  1997;29:413-580.

CYP3A4 Genetic Polymorphisms, Cytochrome P450, CYP450, 3A4 Enzyme