only 30 - 60 per cent of patients respond properly to treatment with antidepressants , beta - blockers , statins and antipsychotic agents . approximately two days of prolonged hospital visits are caused by adverse drug reactions ( adrs ) , and , in the usa , about 100,000 deaths are estimated to be due to adrs every year . these data emphasise an important problem that can be mostly explained by variable pharmacokinetics due , to a large extent , to differences in the activity of cytochrome p450 ( cyp ) enzymes involved in the metabolism of the drugs . variable metabolism , in turn , can be caused by variation in the cyp genes , as is the focus of the current review . there are 57 active cyp genes in the human genome , which are divided into 18 families . the first three families ( cyp1 - 3 ) are generally involved in the metabolism of exogenous substances such as drugs , whereas cyp families with higher numbers are usually involved in the metabolism of endogenous substances . cyp enzymes are responsible for 75 - 80 per cent of all phase i - dependent metabolism and for 65 - 70 per cent of the clearance of clinically used drugs . variation in cyp genes results in phenotypes classically defined as ultrarapid , extensive , intermediate and poor metabolisers . an ultrarapid metaboliser ( um ) generally carries duplicated or multi - duplicated gene copies of the same allele , whereas intermediate ( i m ) and poor metabolisers ( pm ) characteristically carry one and two defective alleles ( eg gene inactivation or deletion ) , respectively . the term extensive metaboliser ( em ) is normally used for subjects carrying two alleles giving normal activity of the cyp enzyme ( also called the * 1 or consensus allele ) . the metaboliser phenotypes are mainly used for describing drug metabolism , but genetic variation in cyps with endogenous functions , such as in sterol , steroid , bile acid and fatty acid homeostasis , have also been well characterised , some of which give rise to disease states . cyp3a4 accounts for about 50 per cent of all cyp - dependent drug metabolism , although individuals ' capacity for cyp3a4-mediated drug metabolism is highly variable . no common genetic variants can account for this variation , despite the fact that 20 different alleles have been described . by contrast , cyp2c19 and cyp2d6 are highly polymorphic and together account for about 40 per cent of the metabolism of clinically used drugs . in addition , cyp1a2 , cyp2a6 and cyp2b6 are polymorphic enzymes that significantly contribute to xenobiotic metabolism . the characterised genetic polymorphism of these enzymes provides a basis for the possibility to adjust drug dosage and choice of drug therapy according to genotype,[4 - 8 ] which includes avoidance of adrs , since polymorphic cyps are frequently the cause of these , either due to the formation of high levels of metabolites or because of decreased metabolism of the parent drug . important work in the cyp area focused on the identification and characterisation of polymorphic human cyp genes , which , in turn , created the need for a unified nomenclature system . thus , in 1999 , a nomenclature committee was formed with the aim of creating a platform for present and future allele nomenclature . thus , the human cytochrome p450 allele nomenclature ( cyp - allele ) website ( http://www.cypalleles.ki.se/ ) was launched with the purpose of managing allele designations , facilitating rapid online publication and providing a summary of alleles and their associated effects . the nomenclature system chosen for the cyp - allele website was based on recognised nomenclature guidelines [ 9 - 13 ] . currently , the website covers the nomenclature for polymorphic alleles of 29 cyp enzymes and nadph cytochrome p450 oxidoreductase ( por ) ( see table 1 ) . the cyp2b6 , cyp2c9 , cyp2c19 and cyp2d6 genes are particularly polymorphic , all with a high number of functionally different alleles . each of the genes at the cyp - allele website has its own webpage that lists the various alleles with their nucleotide changes , molecular and functional consequences in vitro as well as in vivo , and also publications identifying or characterising the alleles . in addition , links to the national center for biotechnology information ( ncbi ) single nucleotide polymorphism database ( dbsnp ) and papers with allele frequencies are presented . the number of visits is relatively constant over time , about 36,000 per year , and the website is highly cited in publications in the field of pharmacogenomics . polymorphic genes covered on the cyp - allele website examples of some important variant alleles are given , as well as representative substrates the designation of an allele ( such as cyp2b6 * 4 ) ideally requires determination of all sequence variations in the gene , although sequencing the intronic regions is generally not necessary . on the website , a gene is considered as the sequence from 5 kilobases upstream from the transcription start site to 500 base pairs downstream of the last exon . if a regulatory element has been characterised at a more distant part of the gene , however , it too is considered to belong to the gene . all known sequence variations within an allele are described on the cyp - allele website , although new allele numbers are currently only designated for alleles that contain at least one functional variation causing consequences such as amino acid substitutions , translation terminations , splice defects , differential transcription rates etc . nevertheless , the allele is required to be well characterised regarding linkage or lack of linkage of the consequential snp with other nucleotide variations , including those in exons , intron - exon junctions and flanking regions . inferring haplotypes by program analyses is generally avoided , although such alleles have occasionally been included on the cyp - allele website . when the characterised sequence variant is found in different constellations with non - causative ( eg silent ) ones , the different combinations are defined as sub - alleles and receive letters in addition to the number ( eg cyp2b6 * 4a , cyp2b6 * 4b ) . when several effective polymorphisms are present on the same allele , however , the allelic number given is based on the polymorphism that causes the most severe consequence , such as a splice defect ( eg cyp2c19 * 2a ) , so alleles that additionally contain sequence variants with less severe effects will share the same allele number , together with an additional letter ( eg cyp2c19 * 2b ) . combinations of variants that are also present alone and that are considered similarly effective ( eg different amino acid substitutions ) are given unique allele numbers ( eg cyp2b6 * 6 ) . notably , the earliest described alleles on the website do not follow the nomenclature system , but the allelic designations have remained , for practical reasons . when new alleles are identified , relevant information is sent to the webmaster . inclusion criteria ( http://www.cypalleles.ki.se/criteria.htm ) involve complete characterisation of the gene sequence , covering exons and exon - intron junctions at the minimum , investigation of linkage with other sequence variants and potential in vitro or in vivo findings . it is advised that the authors of a manuscript that describes a novel allele contact the webmaster before submission , in order to review the data and assign a new allele name to be used in the manuscript . usage of star allele designations that have not been approved by the nomenclature committee is strongly discouraged , because of the apparent risk of confusion and of using the same allele name for different variants . all information sent to the webmaster is kept strictly confidential until publication of the manuscript or until the authors request it to be released . thus , there are likely to be allele names designated by the cyp - allele website that have not yet been published , further emphasising the importance of refraining from using unauthorised allele names . the webmaster ( and in rare cases also the editorial and/or advisory board ) reviews the submission to evaluate whether there are enough data to support a new allele designation . only peer - reviewed data are thus published on the cyp - allele website . papers describing additional characterisation of a known allele -- with respect to , for example , in vitro or in vivo activity -- are also peer reviewed and can be linked to the respective allele on the webpage . suggestions of papers that should be included with respect to further characterisation of alleles are appreciated . important work in the cyp area focused on the identification and characterisation of polymorphic human cyp genes , which , in turn , created the need for a unified nomenclature system . thus , in 1999 , a nomenclature committee was formed with the aim of creating a platform for present and future allele nomenclature . thus , the human cytochrome p450 allele nomenclature ( cyp - allele ) website ( http://www.cypalleles.ki.se/ ) was launched with the purpose of managing allele designations , facilitating rapid online publication and providing a summary of alleles and their associated effects . the nomenclature system chosen for the cyp - allele website was based on recognised nomenclature guidelines [ 9 - 13 ] . currently , the website covers the nomenclature for polymorphic alleles of 29 cyp enzymes and nadph cytochrome p450 oxidoreductase ( por ) ( see table 1 ) . the cyp2b6 , cyp2c9 , cyp2c19 and cyp2d6 genes are particularly polymorphic , all with a high number of functionally different alleles . each of the genes at the cyp - allele website has its own webpage that lists the various alleles with their nucleotide changes , molecular and functional consequences in vitro as well as in vivo , and also publications identifying or characterising the alleles . in addition , links to the national center for biotechnology information ( ncbi ) single nucleotide polymorphism database ( dbsnp ) and papers with allele frequencies are presented . the number of visits is relatively constant over time , about 36,000 per year , and the website is highly cited in publications in the field of pharmacogenomics . polymorphic genes covered on the cyp - allele website examples of some important variant alleles are given , as well as representative substrates the designation of an allele ( such as cyp2b6 * 4 ) ideally requires determination of all sequence variations in the gene , although sequencing the intronic regions is generally not necessary . on the website , a gene is considered as the sequence from 5 kilobases upstream from the transcription start site to 500 base pairs downstream of the last exon . if a regulatory element has been characterised at a more distant part of the gene , however , it too is considered to belong to the gene . all known sequence variations within an allele are described on the cyp - allele website , although new allele numbers are currently only designated for alleles that contain at least one functional variation causing consequences such as amino acid substitutions , translation terminations , splice defects , differential transcription rates etc . nevertheless , the allele is required to be well characterised regarding linkage or lack of linkage of the consequential snp with other nucleotide variations , including those in exons , intron - exon junctions and flanking regions . inferring haplotypes by program analyses is generally avoided , although such alleles have occasionally been included on the cyp - allele website . when the characterised sequence variant is found in different constellations with non - causative ( eg silent ) ones , the different combinations are defined as sub - alleles and receive letters in addition to the number ( eg cyp2b6 * 4a , cyp2b6 * 4b ) . when several effective polymorphisms are present on the same allele , however , the allelic number given is based on the polymorphism that causes the most severe consequence , such as a splice defect ( eg cyp2c19 * 2a ) , so alleles that additionally contain sequence variants with less severe effects will share the same allele number , together with an additional letter ( eg cyp2c19 * 2b ) . combinations of variants that are also present alone and that are considered similarly effective ( eg different amino acid substitutions ) are given unique allele numbers ( eg cyp2b6 * 6 ) . notably , the earliest described alleles on the website do not follow the nomenclature system , but the allelic designations have remained , for practical reasons . inclusion criteria ( http://www.cypalleles.ki.se/criteria.htm ) involve complete characterisation of the gene sequence , covering exons and exon - intron junctions at the minimum , investigation of linkage with other sequence variants and potential in vitro or in vivo findings . it is advised that the authors of a manuscript that describes a novel allele contact the webmaster before submission , in order to review the data and assign a new allele name to be used in the manuscript . usage of star allele designations that have not been approved by the nomenclature committee is strongly discouraged , because of the apparent risk of confusion and of using the same allele name for different variants . all information sent to the webmaster is kept strictly confidential until publication of the manuscript or until the authors request it to be released . thus , there are likely to be allele names designated by the cyp - allele website that have not yet been published , further emphasising the importance of refraining from using unauthorised allele names . the webmaster ( and in rare cases also the editorial and/or advisory board ) reviews the submission to evaluate whether there are enough data to support a new allele designation . papers describing additional characterisation of a known allele -- with respect to , for example , in vitro or in vivo activity -- are also peer reviewed and can be linked to the respective allele on the webpage . suggestions of papers that should be included with respect to further characterisation of alleles are appreciated . the cyp - allele website is widely used and well acknowledged within the scientific community . it serves the purpose of a unified and easily accessible nomenclature system for cyp enzymes , as well as for the cyp electron donor por . the purpose of the cyp - allele website is to facilitate rapid online publication as well as providing a summary of the characteristics of specific alleles .
pharmacogenetics affects both pharmacokinetics and pharmacodynamics , thereby influencing an individual 's response to drugs , both in terms of response and adverse reactions . within the area of pharmacogenetics , findings of genetic variation influencing drug levels 
 have been more prevalent , and variation in the cytochrome p450 ( cyp ) enzymes is one of the most common causes . 
 much of the work concerning sequence variations in cyps aims at finding biomarkers of use for individualised treatment , thereby increasing the treatment response , lowering the number of side effects and decreasing the overall cost of treatment regimens . 
 for over ten years , the human cytochrome p450 allele nomenclature ( cyp - allele ) website ( http://www.cypalleles.ki.se/ ) has offered a database of genetic information on cyp variants , along with effects at the molecular as well as clinical level . 
 thus , this database serves as an assembly of past , current and soon - to - be published information on cyp alleles and their outcome effects . 
 the website is used by academic researchers and companies ( eg as a tool in drug development and for outlining new research projects ) . by providing peer - reviewed genetic information on cyp enzymes , 
 the cyp - allele website has become increasingly popular and widely used . 
 recently , nadph cytochrome p450 oxidoreductase ( por ) , the electron donor for cyp enzymes , was included on the website , which already contains 29 cyp genes , hence por alleles are now also designated using the star allele ( por * ) nomenclature . 
 although most cyps on the cyp - allele website are involved in the metabolism of xenobiotics , polymorphic enzymes with endogenous functions are also included . 
 each gene on the cyp - allele website has its own webpage that lists the different alleles with their nucleotide changes , their functional consequences and links to publications in which the allele has been identified and/or characterised . 
 thus , the cyp - allele website offers a rapid online publication of new alleles , as well as providing an overview of peer - reviewed data .