Genotyping of human CYP3A4

Abstract

Genetic polymorphisms are identified in the human CYP3A4 gene that alter CYP3A4-dependent drug metabolism. Nucleic acids comprising the polymorphic sequences are used to screen patients for altered metabolism for CYP3A4 substrates, potential drug-drug interactions, and adverse/side effects, as well as diseases that result from environmental or occupational exposure to toxins. The nucleic acids are used to establish animal, cell and in vitro models for drug metabolism.

What is claimed is:  
     
         1 . An isolated nucleic acid molecule comprising a CYP3A4 sequence polymorphism, as part of other than a naturally occurring chromosome.  
     
     
         2 . The isolated nucleic acid of  claim 1 , wherein said nucleic acid comprises the nucleotide sequence as set forth in SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, or SEQ ID NO: 58.  
     
     
         3 . The isolated nucleic acid of  claim 1 , wherein said nucleic acid is a hybridization probe of at least 18 nucleotides in length.  
     
     
         4 . The isolated nucleic acid of  claim 3 , wherein said probe is conjugated to a detectable marker.  
     
     
         5 . An array of oligonucleotides comprising: 
 at least one probe of  claim 3  for detection of CYP3A4 locus polymorphisms.    
     
     
         6 . A method for detecting in an individual a polymorphism in CYP3A4 metabolism of a substrate, the method comprising: 
 analyzing the genome of said individual for the presence of at least one CYP3A4 polymorphism listed in Table 3; wherein the presence of said predisposing polymorphism is indicative of an alteration in CYP3A4 expression or activity.    
     
     
         7 . The method of  claim 6 , wherein said analyzing step comprises detection of specific binding between the genomic DNA of said individual with a probe according to  claim 3 .  
     
     
         8 . The method of  claim 6 , wherein said analyzing step comprises detection of specific binding between the genomic DNA of said individual with an array according to  claim 5 .  
     
     
         9 . The method of  claim 6 , wherein said alteration in CYP3A4 expression is tissue specific.  
     
     
         10 . The method of  claim 6 , wherein said alteration in CYP3A4 expression is in response to a CYP3A4 modifier.  
     
     
         11 . The method of  claim 10 , wherein said modifier induces CYP3A4 expression.  
     
     
         12 . The method of  claim 10 , wherein said modifier inhibits CYP3A4 expression.