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the cytochrome p450 ( cyp ) enzymes are active in the metabolism of xenobiotics , as well as of endogenous compounds . in the human genome , 57 genes coding for active cyp enzymes and 58 pseudogenes have been identified .
the cyp enzymes can be divided into two major classes : those that are active in the metabolism of exogenous chemicals , preferentially members of families 1 - 3 , and those that are mainly active in the metabolism of endogenous compounds , in particular steroids , fatty acids , cholesterol and cholesterol derivatives .
many of the active genes are highly polymorphic , as summarised on the human cytochrome p450 allele nomenclature ( cyp - allele ) website http://www.cypalleles.ki.se/ , and several hundred different variants have been identified .
the most polymorphic gene among cyps important for the metabolism of exogenous compounds is the cyp2d6 gene , for which about 80 different allelic variants have been described .
other genes that are highly polymorphic in this gene family are cyp2c9 and cyp2c19 , while other genes with important functional polymorphisms are cyp1a2 , cyp1b1 , cyp2a6 , cyp2a13 , cyp2b6 , cyp2c8 , cyp2j2 , cyp2r1 , cyp2w1 , cyp3a4 , cyp3a5 , cyp3a7 , cyp4a22 , cyp4b1 , cyp4f2 , cyp5a1 , cyp8a1 , cyp19a1 , cyp21a2 and cyp26a1 .
the highest number of variant alleles among the cytochromes p450 is seen in cyp21a2 , which encodes the steroid 21 hydroxylase , for which 119 rare variants have been identified .
in addition to the cyps , nadph cytochrome p450 reductase ( por ) , the electron donor for cyp enzymes , has been shown to have important polymorphic variants http://www.cypalleles.ki.se/por.htm and , recently , the second electron donor , cytochrome b5 , has also been shown to exhibit functional polymorphisms ,   although functionally variant alleles are rare . in the field of pharmacogenetics , emphasis is put on the functionally important polymorphic cyp variants .
this includes about 400 different alleles with non - synonymous mutations or important functional mutations ; 79 , 253 , 34 and 25 variants are present in gene families cyp1 , cyp2 , cyp3 and cyp4 , respectively http://www.cypalleles.ki.se .
the majority of the mutations of functional importance cause stop codons , non - synonymous mutations and splice defects .
the variant alleles have , to a large extent , been identified based on an altered in vivo phenotype within a specific individual .
in addition , targeted sequence screening projects have been carried out to search for non - synonymous mutations that have been expressed in heterologous systems and characterised functionally .
the cyp alleles known so far have generally not been identified through large genomic sequencing projects .
results from such studies are expected to be published in the near future and to yield a high number of novel polymorphic loci . in the authors ' laboratory , for example
, the korean genome has been aligned with the caucasian genome for identification of mutations in the cyp2c locus .
it is evident that thousands of mutations are localised in introns and gene - flanking regions which are not present in the current databases ( frank nyln , unpublished observations ) .
among the p450 genes , only 15 different alleles with intronic mutations causing functional alterations have been identified so far ( see table 1 ) .
the majority are the result of sequencing efforts using genomic dna from individuals shown to have altered cyp activity in vivo . among these mutations , all
intronic polymorphism of the cytochrome p450 genes and of nadph cytochrome p450 reductase ( por ) * a in translational start codon atg is denoted + 1 . * * the i2 splice variant is found in several different alleles among the mutations listed in table 1 , several occur in the cyp21a2 gene , are rare and have been found because of loss of gene function causing congenital adrenal hyperplasia ; however , intronic polymorphisms only account for 5 per cent of all functionally important mutations in this gene .
intron mutations in the p450 genes encoding drug metabolising enzymes have been found in the cyp1a2 , cyp2d6 , cyp2c19 and cyp3a5 genes .
the cyp1a2 * 7 allele , which has a mutation disrupting the splice donor site in intron 6 , has only been identified in one single individual and not been considered in the literature after the initial identification .
the same is also true for cyp2c19 * 7 , which contains a single t > a nucleotide transversion in the invariant gt at the 5 ' donor splice site of intron 5 , causing no functional protein to be expressed .
by contrast , the intron mutations in the cyp2d6 and cyp3a5 genes are much more important .
the cyp2d6 * 4 allele was the first defective cyp2d6 variant allele to be identified ( in 1990 ) , and constitutes the main explanation for the poor metaboliser ( pm ) phenotype among caucasians .
many of the other mutations present in this allele are also present in the partially defective cyp2d6 * 10 allele .
the cyp2d6 * 10 allele is the most common cyp2d6 variant in many asian populations .
it is likely that this intronic mutation was introduced into the cyp2d6 * 10 allele in the past 10,000 to 20,000 years .
the cyp2d6 * 41 allele carries a 2988 g > a mutation in intron 6 , creating an alternate splice donor site .
the cyp2d6 * 41 allele has a very high sequence homology with cyp2d6 * 2 , but early investigations regarding the functional properties of the cyp2d6 * 2 allele revealed heterogeneous activity .
much later on , toscano and collaborators showed the functional properties of the cyp2d6 * 41 allele giving rise to reduced enzyme activity expressed heterologously in cos-1 and huh-7 cells .
the extent of the decrease in activity caused by this allele is important , and carriers who are homozygous for cyp2d6 * 41 have a reduced activity similar in magnitude to those who are heterozygous for a defective cyp2d6 allele .
in addition to the cyp2d6 * 41 allele , gaedigk et al . identified a similar rare variant , named cyp2d6 * 69 , carrying an additional non - synonymous mutation .
the metabolism of clinically important drugs is primarily carried out by the cyp3a4 and cyp3a5 enzymes .
the cyp3a4 gene is very well conserved , and no common functionally important variant allele has been identified .
based on phenotype differences between individuals , kuehl and collaborators sequenced the cyp3a5 gene and identified the variant allele cyp3a5 * 3 with a 6986a > g mutation creating an alternate splice acceptor site in intron 3 . prior to identifying the real background for the defective cyp3a5 allele , several mutations in the 5'-region were thought to form the genetic basis for the reduced cyp3a5 expression .
also the cyp3a5 * 5 allele with a 12952 t > c mutation that results in a disruption of the splice donor site in intron 5 was found in the chinese .
interestingly , the cyp3a5 * 3 and cyp3a5 * 5 alleles are much less common in african populations , causing an overall higher capability for cyp3a - dependent hydroxylase activities .
since cyp3a5 is also expressed in the foetal liver , this polymorphism additionally creates a higher detoxifying potential in foetuses of african origin . in conclusion ,
the intronic polymorphisms in the cyp genes account for only a small number of the important variant alleles .
their discoveries have been based on phenotypic alterations within individuals in a population , and their identification has , in several cases , been difficult and taken a long time . as a result of the next - generation sequencing projects , it is anticipated that new , important information regarding the intron sequence variability among the cyp genes will be discovered , and that further alleles will be identified that can explain the hitherto unidentified genetic basis of inter - individual differences in cyp - mediated drug and steroid metabolism .
the cyp2d6 * 4 allele was the first defective cyp2d6 variant allele to be identified ( in 1990 ) , and constitutes the main explanation for the poor metaboliser ( pm ) phenotype among caucasians .
many of the other mutations present in this allele are also present in the partially defective cyp2d6 * 10 allele .
the cyp2d6 * 10 allele is the most common cyp2d6 variant in many asian populations .
it is likely that this intronic mutation was introduced into the cyp2d6 * 10 allele in the past 10,000 to 20,000 years .
the cyp2d6 * 41 allele carries a 2988 g > a mutation in intron 6 , creating an alternate splice donor site .
the cyp2d6 * 41 allele has a very high sequence homology with cyp2d6 * 2 , but early investigations regarding the functional properties of the cyp2d6 * 2 allele revealed heterogeneous activity .
much later on , toscano and collaborators showed the functional properties of the cyp2d6 * 41 allele giving rise to reduced enzyme activity expressed heterologously in cos-1 and huh-7 cells .
the extent of the decrease in activity caused by this allele is important , and carriers who are homozygous for cyp2d6 * 41 have a reduced activity similar in magnitude to those who are heterozygous for a defective cyp2d6 allele .
in addition to the cyp2d6 * 41 allele , gaedigk et al . identified a similar rare variant , named cyp2d6 * 69 , carrying an additional non - synonymous mutation .
the metabolism of clinically important drugs is primarily carried out by the cyp3a4 and cyp3a5 enzymes .
the cyp3a4 gene is very well conserved , and no common functionally important variant allele has been identified .
based on phenotype differences between individuals , kuehl and collaborators sequenced the cyp3a5 gene and identified the variant allele cyp3a5 *
3 with a 6986a > g mutation creating an alternate splice acceptor site in intron 3 . prior to identifying the real background for the defective cyp3a5 allele
, several mutations in the 5'-region were thought to form the genetic basis for the reduced cyp3a5 expression .
also the cyp3a5 * 5 allele with a 12952 t > c mutation that results in a disruption of the splice donor site in intron 5 was found in the chinese .
interestingly , the cyp3a5 * 3 and cyp3a5 * 5 alleles are much less common in african populations , causing an overall higher capability for cyp3a - dependent hydroxylase activities .
since cyp3a5 is also expressed in the foetal liver , this polymorphism additionally creates a higher detoxifying potential in foetuses of african origin . in conclusion ,
the intronic polymorphisms in the cyp genes account for only a small number of the important variant alleles .
their discoveries have been based on phenotypic alterations within individuals in a population , and their identification has , in several cases , been difficult and taken a long time . as a result of the next - generation sequencing projects , it is anticipated that new , important information regarding the intron sequence variability among the cyp genes will be discovered , and that further alleles will be identified that can explain the hitherto unidentified genetic basis of inter - individual differences in cyp - mediated drug and steroid metabolism .
the research in the author laboratory is supported by grants from the swedish research council , the swedish cancer fund and by vinnova .
the cytochrome p450 enzymes active in drug metabolism are highly polymorphic . 
 most allelic variants have been described for enzymes encoded by the cytochrome p450 family 2 ( cyp2 ) gene family , which has 252 different alleles . 
 the intronic polymorphisms in the cytochrome p450 genes account for only a small number of the important variant alleles ; however , the most important ones are cyp2d6 * 4 and cyp2d6 * 41 , which cause abolished and reduced cyp2d6 activity , respectively , and cyp3a5 * 3 and cyp3a5 * 5 , common in caucasian populations , which cause almost null activity . 
 their discoveries have been based on phenotypic alterations within individuals in a population , and their identification has , in several cases , been difficult and taken a long time . in light of the next - generation sequencing projects , it is anticipated that further alleles with intronic mutations will be identified that can explain the hitherto unidentified genetic basis of inter - individual differences in cytochrome p450-mediated drug and steroid metabolism .