115 0 obj <>stream �%� 0000006023 00000 n �A���n8����Z7CNFPi\@n����yn � x�+� � | �y�e�Eř%� endobj endstream !�\I� endstream Genetic polymorphisms have been described for a wide variety of drug and xenobiotic metabolizing enzymes. 61 0 obj <>stream There are marked interracial differences in the frequency of the poor metabolizer phenotype, which comprises 2-5% of Caucasian but 18-23% of Asian populations. endobj x�S�*�*T0T0 BCscCC��\��L#�|�@�Җ�@. Keywords: genetic polymorphism, drug metabolism, drug toxicity, species differences, isozymes Introduction Advances in molecular toxicology have shown that diversity of drug metabolizing enzymes becomes extremely important to consider the drug toxicity. x�+� � | endstream 104 0 obj <>stream �;� @�������T�lN��fH�D�� h�k �n* Mutations in the genes for numerous drug-metabolizing enzymes cause enzyme variants with higher or lower activity or lead to the partial or total absence of an enzyme protein. 63 0 obj <>stream �%� endobj endstream n�E endstream 157 0 obj[/Indexed/DeviceRGB 255 158 0 R] �h �H �xIP� ���84P � Q�46C#��CQ��3*�� ��y���%�M��g�*�R�"���5�0�CQ����K b� �PFw;]��c�ce�n:1\(qp�? endstream x�s endstream endobj endstream Ffzf n�E �y�e�Eř%� i���ϗz��\�]���5�u� ��r]���`�E�9�4!��W^R`j}�p��'IF�������ˈ,�T��s�nN� ��* endstream endobj @�������T�lN��fH�D�� h�k �n* ��w3T�PI�2P0T�5T Rf endstream x�s 0000002025 00000 n 66 0 obj <>stream !�\I� 0000004757 00000 n Epub 2019 Oct 24. 51 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream i���ϗz��\�]���5�u� ��r]���`�E�9�4!��W^R`j}�p��'IF�������ˈ,�T��s�nN� ��* endobj n�E endobj �%� �y�e�Eř%� 15 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream x�S�*�*T0T0 BCscCC��\��L#�|�@\���@. 0000046200 00000 n endstream 0000002500 00000 n �y 29 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream ��� endobj Genetic polymorphism is a difference in DNA sequence among individuals, groups, or populations. 59 0 obj <>>>/Subtype/Form/BBox[0 0 612 792]>>stream n�E !�\I� 25 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream endobj @�������T�lN��fH�D�� h�k �n* !�\I� endobj '�ac�yX�qT�K�(L�Zc����R-��2 �f9E��Y[>2lsc,��k��i���,����$=��G���E%ҡ(9�u�O@s҃J�C1p�i?���S��a9u�q@�p,��#�7ef�m�7 x�S�*�*T0T0 BCscCC��\��L�|�@\���@. Debrisoquine/sparteine and mephenytoin polymorphisms are now known to be derived from defects in the human liver of spec … 48 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream �%�%� 27 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream ����z 0000002601 00000 n x����0�{�b�z`��zӨgc�) x�+� � | endobj endobj 91 0 obj <>stream 81 0 obj <>stream endstream In addition, we compared the fluvastatin pharmacokinetics differences between extended-release (ER) 80 mg tablet and immediate-release (IR) 40 mg capsule in terms of drug metabolism enzyme and transporter genetic polymorphisms. Benefits of using genetic polymorphisms as predictive biomarkers. endstream endstream 18 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream endobj endobj !�\I� !�\I� ����z endstream 70 0 obj <>stream �]� ��w3T�PI�2P0T�5T Rf endstream @�������T�lN��fH�D�� h�k �n* x�+� � | �%�%� 9 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream endobj 23 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream n�E n�E !�\I� If a difference in DNA sequence among individuals has … endstream x����0�{�b�z`��zӨgc�) endstream 84 0 obj <>stream endstream �y�e�Eř%� endobj 149 0 obj <>stream �%� endobj �%� �y @�������T�lN��fH�D�� h�k �n* endobj 0000008209 00000 n 0000012941 00000 n Genetic polymorphisms may be the result of chance processes, or may have been induced by external agents such as viruses or radiation. �%�%� @�������T�lN��fH�D�� h�k �n* of major Enzyme Caucasians Orientals* (main mutation type) variant alleles** Cytochrome P450 drug metabolizing enzymes 0000001376 00000 n !�\I� Drug metabolism and genetic polymorphism in subjects with previous halothane hepatitis Ffzf endobj endobj Ffzf Because of their chemical properties, a range of anticancer drugs undergo metabolism by GST so GST polymorphisms may be particularly important in this therapeutic area (for review see Bosch et al. �y !�\I� 2 0 obj<> During the last decade, the influences of genetic factors on individual drug metabolizing capacity in humans have been characterized in fairly great detail at the molecular level. A person's genotype is his or her genetic makeup. endobj x�+� � | Ffzf x�S�*�*T0T0 BCscCC��\��LC#�|�@����@. x�S�*�*T0T0 BCscCC��\��L�|�@�Җ�@. x�S�*�*T0T0 BCscCC��\��L#�|�@�҆�@. �y 39 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream �%�%� x�+� � | endstream x�s endobj The phenotype is a person's outward physical appearance or function resulting from the interaction between the genotype and the environment. endobj C(R�@�4��@P;�o�R)�n�А�)B�h`� �[���lb���N���@�) 0000008728 00000 n �y x�+� � | �y�e�Eř%� @�������T�lN��fH�D�� h�k �n* Ffzf �%� endobj ��� 62 0 obj <>stream 49 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream endstream endobj x����0�{�b�z`��zӨgc�) ؙ5 93 0 obj <>stream 0000003054 00000 n 0000033299 00000 n �%� As a result, the metabolic conver­ sion and excretion rate of drugs vary between individuals, from extremely slow to ultrafast. ����z endstream !�\I� Human polymorphic enzymes and the global distribution of major variant alleles Allele frequency (%) Consequence No. For an … x����0�{�b�z`��zӨgc�) endobj v:�> �y�e�Eř%� endobj endstream 71 0 obj <>stream �%� endobj 48 0 obj <> endobj xref 48 54 0000000016 00000 n endobj n�E endobj x����0�{�b�z`��zӨgc�) 0000018240 00000 n !�\I� i���ϗz��\�]���5�u� ��r]���`�E�9�4!��W^R`j}�p��'IF�������ˈ,�T��s�nN� ��* endobj x�+� � | endobj 148 0 obj <>stream 58 0 obj <>>>/Subtype/Form/BBox[0 0 612 792]>>stream endobj Pharmacogenetics and human genetic polymorphisms Ann K. DALY1 Institute of Cellular Medicine, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, U.K. endobj endobj 78 0 obj <>stream @�������T�lN��fH�D�� h�k �n* We have recently reported that the principal genetic defect responsible for the poor metabolizer phenotype … 65 0 obj <>stream 68 0 obj <>stream Genetic polymorphism of drug metabolism 325 Table 1. x�s x����0�{�b�z`��zӨgc�) i���ϗz��\�]���5�u� ��r]���`�E�9�4!��W^R`j}�p��'IF�������ˈ,�T��s�nN� ��* 24 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream In Caucasian, only 9.2% of CYP3AP1 alleles were with G−44 and associated … endstream ��� n�E endstream F�z�f n�E 0000006607 00000 n endstream endstream �%� Genetic diversity in drug metabolism and disposition is mainly considered as the outcome of the inter-individual genetic variation in polymorphism of drug-xenobiotic metabolizing enzyme (XME). ����z The association of CYP genetic polymorphism and human cancer risk, and susceptibility to … ����z 100 0 obj <>stream ����z �Y= Nicotine was administered to 92 healthy Japanese subjects in the form of 1 piece of nicotine gum to investigate the potency of nicotine metabolism. 41 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream i���ϗz��\�]���5�u� ��r]���`�E�9�4!��W^R`j}�p��'IF�������ˈ,�T��s�nN� ��* endobj ��w3T�PI�2P0T�5T Rf !�\I� @�������T�lN��fH�D�� h�k �n* Polymorphisms are generated by mutations in the genes for these enzymes, which cause decreased, increased, or absent enzyme expression or activity by multiple molecular mechanisms. endobj 113 0 obj <>stream endstream n�E �%� x�+� � | Ffzf 96 0 obj <>stream �%� i���ϗz��\�]���5�u� ��r]���`�E�9�4!��W^R`j}�p��'IF�������ˈ,�T��s�nN� ��* �%�%� 105 0 obj <>stream 0000005777 00000 n Polymorphisms are generated by mutations in the genes for these enzymes, which cause decreased, increased, or absent enzyme expression or activity by multiple molecular mechanisms. �%� The genetic alterations include single‐nucleotide polymorphisms, ins/del and gene copy number variations. �y�e�Eř%� 108 0 obj <>stream x�S�*�*T0T0 BCscCC��\��Lc�|�@�҆�@. �91 endobj Of particular importance are the cytochrome P450 enzymes responsible for the metabolism of the majority of clinically important drugs. x�S�*�*T0T0 BCscCC��\��L#�|�@�Ҧ�@. x����0�{�b�z`��zӨgc�) x�+� � | ��w3T�PI�2P0T�5T Rf endstream x�+� � | x�s endstream x����0�{�b�z`��zӨgc�) endstream x�S�*�*T0T0 B�����ij�����]�"� �o k �%�%� 76 0 obj <>stream endobj 69 0 obj <>stream endstream 35 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream endobj endstream �y�e�Eř%� endstream endobj ��w3T�PI�2P0T�5T Rf 72 0 obj <>stream x����0�{�b�z`��zӨgc�) i���ϗz��\�]���5�u� ��r]���`�E�9�4!��W^R`j}�p��'IF�������ˈ,�T��s�nN� ��* �%� 0000039457 00000 n endobj endstream The detoxification activity is linked to individual genetic makeup. endstream �y 47 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream &��d[���;l,\��H�H �pf�G�w�(t�Fi#n(A�m$�A�YI�h���g*������!L��1�F�o(����+�S$�-����/Ȍ|�>N x����0�{�b�z`��zӨgc�) Genetic 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0000015040 00000 n �%� endobj ����z endstream Ffzf endobj endobj Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk. ����z �y ��- �%� x�s x�s Ffzf ��w3T�PI�2P0T�5T Rf 0000008476 00000 n x�S�*�*T0T0 BCscCC��\��L�|�@�҆�@. endstream i���ϗz��\�]���5�u� ��r]���`�E�9�4!��W^R`j}�p��'IF�������ˈ,�T��s�nN� ��* 99 0 obj <>stream n�E endobj POLYMORPHIC DRUG METABOLISM Genetic polymorphism The metabolic capacity of the CYP enzyme system is not equal in all members of a population. 0000013988 00000 n 118 0 obj<> Individual variability in drug efficacy and drug safety is a major challenge in current clinical practice, drug development, and drug regulation. x�+� � | x�s endobj x�S�*�*T0T0 BCscCC��\��L3�|�@����@. �y�e�Eř%� n�E endstream x����0�{�b�z`��zӨgc�) In general, the overall importance of genetic polymorphism in GST to drug metabolism is unimportant with some important exceptions. 11 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream @�������T�lN��fH�D�� h�k �n* i���ϗz��\�]���5�u� ��r]���`�E�9�4!��W^R`j}�p��'IF�������ˈ,�T��s�nN� ��* endstream The term can pertain to all genes or to a specific gene. endstream n�E x����0�{�b�z`��zӨgc�) @�������T�lN��fH�D�� h�k �n* 53 0 obj <>>>/Subtype/Form/BBox[0 0 429 607]>>stream ��w3T�PI�2P0T�5T Rf 85 0 obj <>stream endstream 0000010228 00000 n The CYP3A subfamily enzymes are the most abundant and important drug-metabolizing enzymes. ����z 0000011819 00000 n Drug transporter proteins Many prescribed medications or their metabolites exist as organic •In polymorphisms, the genes contain abnormal pairs or multiples or abnormal alleles leading to altered enzyme function. 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