Polymorphisms and other familial factors related to enzymes metabolising drugs and xenobiotic chemicals are good known. This article focuses on polymorphism in the xenobiotic drug metabolising enzymes peculiarly cytochromes P-450 ( CYP ) as illustration of stage I enzymes and N-acetyl transferases as illustration of stage II enzymes and distribution of variant signifiers of these enzymes in different cultural groups.The cytochrome P450 ( CYP ) enzyme system is involved in the metamorphosis and riddance of figure of widely used drugs. The capacity of this system varies from one individual to another, taking to variable drug elimination rates and intersubject differences in the concluding serum drug concentrations.
For this ground, curative response and side-effects vary widely between patients treated with the same dosage of drug. The intersubject variableness in metabolic rate is mostly determined by familial factors. Some CYP enzymes including CYP2D6, CYP2C9 and CYP2C19 are genetically polymorphous. Similarly N-acetyltransferase enzyme is genetically polymorphous. Several mutant allelomorphs have been described. All the major human drug-metabolizing P450 enzymes have been identified, and the major cistron discrepancies that cause inter-individual variableness in drug response and are related to inauspicious drug reactions have been identified.
This information now provides the footing for the usage of prognostic pharmacogenetics to give drug therapies that are more efficient and safer.
Keywords: Familial polymorphism, Cytochrome P450, N-acetyltransferase.
Inter-individual fluctuation in drug response among patients is good known and poses a serious job in medical specialty. There are no biomarkers at present that can foretell which group of patients responds positively, which patients are nonresponders and who experiences inauspicious reactions for the same medicine and dosage. Many different enzymes are involved in the metamorphosis of chemical substances, but the focal point of this overview will be on members of the cytochrome P450 household of enzymes andA N-acetyltransferases ( NAT ) . Many of the enzymes involved in the metamorphosis show a polymorphous distribution, and the familial footing for some of these polymorphisms has been identified ( Herman A, 2000 ) . Among drug metabolising enzymes, cytochrome P450 ( CYP ) proteins are heme-containing enzymes. They are good known for their oxidative debasement of endogenous chemicals present in the diet, environment and medicines. There are every bit many as 57 CYP cistrons and among them three households of cistrons – CYP1, CYP2 and CYP3-are the major cistrons ( Wilkinson GR 2005 ) . lending to the oxidative metamorphosis of assorted compounds. NATs catalyze the acetylation of carcinogens and other xenobiotics including Arylamines, hydrazines and hydrazides are metabolized by NAT-mediated N-acetylation. The NAT venue on human chromosome 8p ( 21.3-23.1 ) ( Hickman D et. al.,1994 ) encodes three distinguishable NAT cistrons, the two active NAT cistrons, monomorphic NAT1 ( Blum M. et al. , 1990 ) and polymorphous NAT2 ( Grant DM 1989 ) , separated by an inactive pseudogene. Large interindividual fluctuation in these two enzymes has been observed in human which is described in this reappraisal.
Familial polymorphism in CYP P- 450 system:
The most of import enzymes accounting for fluctuation in stage I metamorphosis of drugs is the cytochrome P-450 enzyme group, ( Ingelman-Sundberg M. 2004 ; Weinshilboum R, 2003 ) which exists in many signifiers among persons because of familial differences. The cytochrome P450 enzymes in households 1-3 mediate 70-80 % of all stage I-dependent metamorphosis of clinically used drugs ( Bertz R.J. and Granneman G.R,1997 ; Evans W.E. and Relling M.V, 1999 ) and take part in the metamorphosis of a immense figure of xenobiotic chemicals. The polymorphous signifiers of P450s are responsible for the development of a important figure of inauspicious drug reactions ( ADRs ) . Harmonizing to Phillips et Al. ( 2001 ) 56 % of drugs that are cited in ADR surveies are metabolized by polymorphous stage I enzymes, of which 86 % are P450s. The major P450 signifiers that are of import in human drug metamorphosis are shown, together with their belongingss and polymorphisms in table 1.
Table 1. Relative importance of polymorphisms in human cytochrome P450 enzymes involved in drug metamorphosis.
Major allelomorphic variants.a
Clinical consequence of the polymorphism.
Significans of the polymorphism.b
Less enzyme look and induciblity
Altered nicotine metamorphosis of malignant neoplastic disease drug.
Significant for metamorphosis of malignant neoplastic disease drugs.
Altered taxol metamorphosis
Drug dose, drug efficaciousness
No conclusive survey
No conclusive survey
No conclusive survey
a A description of the allelomorphs can be found on the human cytochrome P450 allele nomenclature commission place page ( hypertext transfer protocol: //www.imm.ki.se/CYPalleles/ ) . b The signii¬?cance of the polymorphism is based on the figure of studies demoing impact of the P450 polymorphism on the pharmacokinetics of drugs that are substrates for the enzyme in inquiry. Increasing Numberss of ‘ + illustrate the increasing importance of the polymorphism relation to the other signifiers of P450.
Among CYP 450 enzyme system CYP2C9, CYP2C19 and CYP2D6 are extremely polymorphous and accounts together for approximately 40 % of hepatic human stage I metabolism. The functional importance of the variant allelomorphs, nevertheless, differs and the frequences of their distribution in different cultural groups besides differ. As a consequence, the metabolic transition and elimination rate of drugs vary between persons, from highly slow to ultrafast. For many drugs, four major phenotypes can be distinguished: hapless metabolizers ( PMs ) , intermediate metabolizers ( IMs ) , extended metabolizers ( EMs ) and ultrarapid metabolizers ( UMs ) . The intersubject variableness in metabolic rate is mostly determined by familial factors. ( May DG, 1994 ; Meyer UA et Al. 1996 ) Genetic fluctuation may bring forth normal enzyme in lessened sums, ill active or inactive enzyme, or monolithic sums of enzyme. A figure of CYP enzymes are known to be genetically polymorphous. Mutant allelomorphs transporting certain nucleotide permutations, omissions, interpolations or cistron transitions are known, which may ensue in CYP enzymes with unnatural activity. ( Weide J and Steijns SW, 1999 ) Some mutations, the alleged nothing allelomorphs, lead to enzyme lack or entire absence of enzyme activity. This genetically determined discrepancy in enzyme activity consequences in the different drug metamorphosis phenotypes.
CYP2D6 Genetic Polymorphism:
Among all CYP enzymes, the extremely genetically polymorphous enzyme debrisoquine-4-hydroxylase, or CYP2D6, has been the most extensively studied. CYP2D6 is involved in the oxidative metamorphosis of more than 40 widely prescribed drugs. The CYP2D6 cistron is localized on chromosome 22q13.1 ( Sachse C et al. , 1997 ) . The CYP2D6 cistron contains nine coding DNAs within a sum of 4378 base brace. The venue contains two neighbouring pseudogenes, CYP2D7 and CYP2D8 ( Eim MH, Meyer UA, 1992 ) . The development of the human CYP2D venue has involved riddance of three cistrons and inactivation of two ( CYP2D7P and CYP2D8P ) and partial inactivation of one ( CYP2D6 ) . At present, more than 50 known different major polymorphous CYP2D6 allelomorphs are known ( Marez D,1997 ; Sachse C, 1997 ) . The presence of the extremely similar closely located pseudogenes transporting damaging mutants have through, for illustration, unequal crossing over reactions led to the formation of many of the variant CYP2D6 allelomorphs, which most normally encode faulty cistron merchandises. The ‘activity ‘ in the CYP2D venue is high as compared to, for illustration, the CYP2C venue and as a consequence many discrepancy allelomorphs have been formed in a comparatively short period of clip. The variant CYP2D6 allelomorphs can be classified into classs, which cause abolished, decreased, normal, increased or qualitatively altered cataxlytic activity. Among the most of import discrepancy 1s are CYP2D6*2, CYP2D6*4, CYP2D6*5, CYP2D6*10, CYP2D6*17. For farther inside informations see table 2.
Table 2 Major human polymorphous discrepancy CYP2D6 allelomorphs and their planetary distribution.
Allele frequences ( % )
Gene duplicatio/ multiduplication
Increased enzyme activity
T107I, R296C, S486T
Altered affinity for substrates
20-35Data is summarised from hypertext transfer protocol: //www.imm.ki.se/cypalleles/cyp2d6.htm and Bradford 2002 For farther allelomorph frequences in different populations, see Bradford 2002.
The most common allelomorph in Asians ( allele frequence of 450 % ) and therefore possibly the most common CYP2D6 allelomorph in the universe is CYP2D6*10. ( Johansson I, et al. , 1994 ) Five to 10 % of Caucasians lack CYP2D6 activity wholly because of the heritage of two mutant CYP2D6 nothing allelomorphs. These topics are classifieded as PMs, with an impaired metamorphosis of CYP2D6 substrates ( Alvan G, et al 1990 ) . The bulk of faulty allelomorphic discrepancies of the CYP2D6 cistron that give rise to the PM phenotype have now been identified. Up to 7 % of Caucasians are UMs of CYP2D6 substrates, owing to the heritage of allelomorphs with duplicate or elaboration of functional CYP2D6 cistrons, doing an inordinate sum of enzyme to be expressed ( Johansson I, et al. , 1993 ; Agundez JAG et al,1995 ) . The metabolic capacity of the remainder of the population lies someplace between the extremes. IMs have mutants on the CYP2D6 cistron, which cause merely a partial lessening in enzyme activity. Subjects who are either homozygous for the normal-functioning allelomorphs, or heterozygous with one active and one defect allelomorph, are classified as EMs. Among EMs, metabolic rate can run well. In topics homozygous for the active allelomorphs, CYP2D6 drugs are metabolized more expeditiously than the heterozygous genotypes. The latter are more at hazard for drug – drug interaction if two or more CYP2D6 drugs have to be administered concomitantly. In general, the drug metamorphosis phenotype is determined by the figure of functional CYP2D6 cistrons nowadays ( Johansson I, et al. , 1993 ; Sachse C et al.,1997 ) . In non-Caucasian populations, PM and UM phenotypes of CYP2D6 substrates may happen with different prevalences. In Orientals, for illustration, there are barely any PMs and UMs, but the frequence of the IM phenotype is really high ( Bertilsson L et al. , 1995 ) . In some African populations, prevalences of up to 29 % for the UM phenotype have been reported ( Alklillu E et al. , 1996 ) . Evaluation of the figure of topics transporting CYP2D6 cistron duplicates in Western Europe reveals that 5.5 % of the Europeans carry more than two active CYP2D6 cistron transcripts and are UMs ( Table 3 ) .
Table 3. An appraisal of the figure of ultrarapid CYP2D6 metabolisers in Western Europe transporting two or more active CYP2D6 cistrons on one allelomorph. The overall per centum in the population is 5.45 %
CYP2C9 Genetic Polymorphism:
CYP2C9 is the major human enzyme of the cytochrome P450 2C subfamily and metabolizes about 10 % of all therapeutically relevant drugs. It constitutes about 20 % of the hepatic cytochrome P450 enzyme expressed in worlds and therefore is responsible for the metamorphosis of a broad spectrum of clinically of import drug ( Takahashi H and Echizen H, 2001 ) . The human CYP2C9 cistron is located on chromosome 10 between q23 and q24 with a length of about 55 kilobits ( Lee CR et al. , 2002 ; Finta C and Zaphiropoulos PG. , 2000 ) . It has been shown to be polymorphous. CYP2C9 polymorphism has contributed to the broad inter-individual pharmacokinetic variableness in footings of drug metamorphosis, for case, S-warfarin ( Takahashi H et al. , 2003 ) , diclofenac ( Dorado P et al. , 2003 ) , losartan ( Odani A et al. , 1997 ) , phenytoin ( Odani A et al. , 1997 ) and tolbutamine ( Shon JH et Al 2002 ) . Therefore far, 12 different discrepancies have been identified. The wild type of allelomorph is identified as CYP2C9*1 and the mutant discrepancies are known harmonizing to an go uping numerical order of CYP2C9*2 to CYP2C9*12 ( Table 4 ) . Although several allelomorphic discrepancies of CYP2C9 have been reported and identified, the most common discrepancies are CYP2C9*2 and CYP2C9*3, apart from the wild type allelomorph. CYP2C9*2 and CYP2C9*3 allelomorphic discrepancies differ from the wild type allelomorph by a individual nucleotide permutation. Two inhereted amino acid permutations, Arg144Cys ( 2* ) and Ile359Leu ( 3* ) , are know to impact catalytic maps of CYP2C9 ( Ieiri I et al. , 2000 ; Sullivan-Klose TH et al. , 1996 ; Tarbit MH and Wolf CR 1996 ) . The consequence of the polymorphism on Coumadin metamorphosis has been studied extensively in the Caucasic population. CYP2C9*3 allelomorph has much lower catalytic activity as compared to the CYP2C9*2 allelomorph ( Dorado P et al. , 2003 ; Aithal GP et al. , 1999 ) . For illustration, a heterozygous discrepancy of CYP2C9*3 has caused a decrease in the clearance of unwritten S-warfarin in vivo by 66 % , whereas the homozygote CYP2C9*3 showed a 90 % decrease in warfarin clearance relation to the wild type of the genotype ( CYP2C9 *1/*1 genotype ) ( Takahashi H et al. , 2003 ) . CYP2C9 polymorphism has been extensively studied in many major populations including the Caucasic, Russian, African, Turkish, Japanese, Korean, and Tamilian Indian. The mutations CYP2C9*2 and CYP2C9*3 are comparatively more often found in Caucasians, whereas they are rare in the Chinese and Nipponese ( Garcia-Martin E et al. , 2001 ) , in table IV allelomorph frequences of the most prevailing allelomorphs are given for the major cultural groups. Variant CYP2C9*2 is about absent in African and Asiatic populations. Besides CYP2C9*2 and *3, many other familial discrepancies have been described within CYP2C ( Lee CR et al. , 2002 ; Dickmann LJ et al. , 2003 ; Kidd RS et al. , 2001 ; Zhao F et al.,2004 ; Sandberg M, 2004 ) but the frequence of most of these allelomorphs is low or the polymorphisms do non take to an amino acerb exchange ( www.imm.ki.se/CYPalleles/CYP2C9.htm ) .
Table 4. Polymorphic discrepancy of CYP2C9 allelomorphs and their planetary distribution.
Summarized frequence informations from ( Lee CR et al. , 2002 ; Blaisdell J et al. , 2004 ; Takanashi K et al. ,
2000 ; Haining RL et al. , 2004 ; Xie HG et al. , 2002 ; Bahadur N et al. , 2002 ; Yasar U et al. , 2002 ; Allabi AC et al. ,
2003 ; Scordo MG et al. , 2001 ; Allabi AC et al.,2004. ) A dash indicates deficiency of sufficient informations. Note that such allele frequences may even differ within the major cultural groups.CYP: Cytochrome P450.
CYP2C19 Genetic Polymorphism:
Cytochrome P450 2C19 ( CYP2C19 ) plays an of import function in the metamorphosis and riddance of a broad scope of medicines such as S-mephenytoin, Valium, Prilosec, proguanil, citalopram, R-warfarin and many antidepressants ( Bertilsson L et al. , 1995 ) . The human CYP2C19 cistron is located on chromosome 10. CYP2C19 is a polymorphically expressed enzyme ( Goldstein JA, 2001 ) . Therefore far, 6 different discrepancies have been identified ( Table 5 ) . The most frequent of these familial polymorphisms are CYP2C19*2, incorporating a G681A point mutant in exon 5 ensuing in a splice defect, and CYP2C19*3, incorporating a G636A passage in exon 4, which produces a premature halt codon. The wild-type allelomorph is referred to as *1. CYP2C19*17 is a freshly identified allele transporting -806C & gt ; T and -3402C & gt ; T.
Table 5. Major human polymorphous discrepancy CYP2C19 allelomorphs.
C99T, A991G, Ile331Val
C99T ; G681A ; C990T ; A991G, Ile331Val. ) .
C99T ; G276C, Glu92Asp ; G681A ; C990T ; A991G ; Ile331Val
C99 ; A991, Ile 331 ; C1297T, Arg433Trp
C99T ; A991G, Ile331Val ; C1297 T, Arg433Trp ) .
C99T ; G395A, Arg132Gln ; A991G, Ile331Val ) .
Summarized informations from ( Romkes M et al.,1991 ; Richardson TH et al. , 1995 ; De Morais SMF et a.,1994 ) .
The polymorphisms of this enzyme give rise to significant inter-individual and inter-ethnic variableness ( table 6 ) . The frequence of hapless metabolizers of CYP2C19 varies between 19-23 % among the Nipponese population, 15 % among the Chinese, and 13 % among Koreans, 2-5 % in Caucasians and 4 % in a Shona population of Zimbabwe. CYP2C19*2 histories for 75 % of CYP2C19 faulty allelomorphs in Orientals, and 93 % in Caucasians. The other good characterized damaging allelomorph ( CYP2C19*3 ) discovered in Nipponese PMs, histories for about 25 % of all inactive signifiers in Orientals, being by converse highly rare in non-Oriental populations.
Table 6. Frequency of the CYP2C19 allelomorphs in different populations.
Summarized frequence informations from ( Ozawa S et al. , 2004 ; Goldstein JA et al. , 1997 )
N-acetyl -transferase ( NAT ) :
NATs are cytosolic enzymes and are found in a big figure of tissues. There exist two functional human arylamine N-acetyltransferases, the polymorphous NAT2 ( Grant DM et al. , 1989 ) and the once named monomorphic NAT1 ( Blum M et al. , 1990 ) . Both cistrons have been assigned to chromosome 8p2l.3-23.1 ( Hickman D et al. , 1994 ) they contain 870-bp intronless protein-coding parts and are separated by 25 a‰? kilobit. In add-on there exists a pseudogene, NATP, which does non encode a functional protein. Both NAT1 and NAT2 cistrons are known to be polymorphous in worlds, matching to decelerate and rapid acetylator phenotypes. Both catalyze the N-acetylation of aromatic aminoalkane and hydrazine drugs. While substrates of NAT2 enzyme are isoniazid, sulfamethazine, 2-aminofluorene and 4-aminobiphenyl, NAT1 enzyme has para-aminosalicylic acid ( PAS ) , para-aminobenzoic acid ( PABA ) and sulfanilamide as substrates. Considerable cultural fluctuation in the NAT activity has been observed, the slow phenotype runing from 90 % in North Africans to 10 % -30 % in Nipponese and Korean Orientals.
NAT1 Genetic Polymorphism:
The polymorphism of NAT1 cistron was foremost described about two decennary ago and 26 allelomorphs have been identified in human populations ( Hein DW et al. , 2000 ) . NAT1*3, NAT1*4, NAT1*5, NAT1*10 and NAT1*11 being the most common allelomorphs reported ( table 7 ) . NAT1*4 allele denoted as the wild-type ( Vatsis KP and Weber W, 1993 ) . The NAT1*3 allelomorph is likely functionally comparable with the NAT1*4 allelomorph, as the mutant does non do an amino acid alteration ( Hirvonen A 1999 ) . The late described NAT1*14 and *17 allelomorphs encode for proteins with decreased acetylation capacity, whereas the NAT1*11 allelomorph is now agreed to be associated with higher NAT1 activity. A individual mutant or a combination of multiple nucleotide permutations and insertions/deletions are responsible for the allelomorphic discrepancies of NAT1.
Table 7. Major human polymorphous discrepancy NAT1 allelomorphs.
Nucleotide Change ( s )
1095C & gt ; A
Equivalent to NAT1*4
350,351G & gt ; C 497-499G & gt ; C 884A & gt ; G.
1088T & gt ; A, 1095C & gt ; A.
Greater than NAT1*4 “ Rapid ”
344C & gt ; T, 40A & gt ; T, 445G & gt ; A, 459G & gt ; A 640T & gt ; G, 1095C & gt ; A
Greater than NAT1*4 “ Rapid ” ?
344C & gt ; T, 40A & gt ; T, 445G & gt ; A, 459G & gt ; A 640T & gt ; G
Greater than NAT1*4 “ Rapid ” ?
-344C & gt ; T -40A & gt ; T 459G & gt ; A 640T & gt ; G
1095C & gt ; A
NAT2 Genetic Polymorphism:
Arylamine N-acetyltransferase 2 ( NAT2 ) is a cytosolic stage II junction enzyme which catalyzes the transportation of an acetyl group from acetyl-CoA to the N or O atom and is responsible for the acetylation of legion xenobiotics and arylamine or hydrazine containing drugs, including TB ( TB ) and acquired immune lack syndrome ( AIDS ) -related therapeutics, such as INH ( INH ) and sulphonamides, and is expressed preponderantly in the liver. The human NAT2 cistron is extremely polymorphous and represents one of the best studied illustrations of the big interindividual variableness of familial control of drug or xenobiotic metamorphosis. Most SNPs ( individual nucleotide polymorphisms ) reported to day of the month are found within the 873 bp intronless coding part of NAT2 cistron, which is located in chromosome 8p22. Analysis of polymorphisms at the NAT2 cistron venue can place persons with rapid, intermediate or slow acetylator phenotypes ( table 8 ) . Among seven major different NAT2 mutants, five led to amino acerb alterations ( Deguchi T et al. , 1990 ) . Each slow allelomorph contains a combination of one or two nucleotide permutations that occur at place 481 ( C to T ; M1 allelomorph ) , 590 ( G to A ; M2 ) , 857 ( G to A ; M3 ) and191 ( G to A ; M4 ) of the cistron 8 which has progressively been recognized as enforcing a higher hazard of clinically important wellness jobs. Harmonizing to the consensus cistron terminology of human NAT2 ( www.louisville.edu/medschool/pharmacology/NAT.html ) , the NAT2 allelomorphs or haplotypes are characterized by the combination of up to four SNPs nowadays in the coding part. Presently, there is a sum of 32 SNPs identified in the NAT2 coding part ( 25 in the terminology functionary site and the other seven in the Entrez SNP database ) with 53 described combinations ( allelomorphs ) . The presence of the NAT2*4 ( wild-type ) allelomorph defines the NAT2 genotype as rapid and combinations of the often happening mutant allelomorphs NAT2*5B, *5C, *6A, *7B, and *14 bunch as slow.
Table 8. Major human polymorphous discrepancy NAT2 allelomorphs.
Nucleotide Change ( s )
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