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Sequence of the human CYP3A locus: Genetic variability and drug responsiveness
  
By
Edward R. Winstead


To identify genetic differences linked to drug responsiveness, German researchers sequenced a region of the human genome containing CYP3A genes, which are involved in the metabolism of most pharmaceuticals. The researchers pinpointed the locations of three previously identified human CYP3A genes and identified one novel member of this gene family. The targeted region of chromosome 7 contains about 230,000 base pairs, and the analysis revealed three pseudogenes, according to a paper describing the research in Pharmacogenetics.



Schematic organization of the human CYP3A gene locus on chromosome 7. Arrows indicate the orientation of the open reading frames of CYP3A genes. Unmarked rectangles depict the three CYP3A pseudogenes found within the locus. Arrowheads indicate duplication boundaries within the locus.

Leszek Wojnowski, of Epidauros Biotechnologie AG, in Bernried, Germany, led the study. There are more than 50 known human cytochrome P450 (CYP) genes, which are classified into families and subfamilies according to sequence similarity. The researchers assigned the newly identified gene, CYP3A43, to the CYP3A subfamily based on the degree of the protein sequence identity, its location within the CYP3A cluster and the conservation of the intron/exon organization, according to the paper.

CYP3A proteins metabolize a range of chemical substances from steroids to antidepressants to immunosuppressive agents. CYP3A genes are expressed in metabolic organs (gastrointestinal tract, liver, and kidney), and their expression levels vary greatly within and between ethnic groups. This variation that may determine whether a patient has a positive or adverse response to a drug.

Cytochrome P450 enzymes are a defense mechanism that protects organisms from naturally occurring toxic chemicals. The enzymes also convert man-made chemicals and drugs into less toxic, more water-soluble products, thereby facilitating their elimination from the body. The enzymes can also transform nontoxic chemicals into reactive intermediates that are toxic or carcinogenic, according to a recent News and Views article in Nature Medicine.

"The variability of CYP3A expression, coupled with the broad spectrum of drugs that are metabolized by CYP3A proteins, creates a potential for harmful drug interactions involving these [enzymes] in patients undergoing therapies with multiple drugs," the researchers write in Pharmacogenetics.

Wojnowski and colleagues sequenced approximately one thousand bacterial clones representing the chromosome region using Perkin Elmer Biosystems capillary 3700 DNA analyzers. This was followed by three rounds of closing gaps in the sequence, which involved additional sequencing, sequence editing and the subsequent assembly using computational tools. The sequencing was completed in 2000, prior to publication of the human genome sequence.

The sequence of the CYP3A locus has been used to screen for sequence variants, or polymorphisms, in CYP3A genes. The results of a first such screen, which describes protein variants of CYP3A4, will be published in the July issue of Pharmacogenetics.

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Gellner, K. et al. Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene. Pharmacogenetics 11, 111-121 (March 2001).
 
Eichelbaum, M. & Burk, O. CYP3A genetics in drug metabolism. Nat Med 7, 285-287 (March 2001).
 

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