Assuntos
Falso Aneurisma , Aneurisma , Implante de Prótese Vascular , Procedimentos Cirúrgicos do Sistema Digestório , Procedimentos Endovasculares , Aneurisma/cirurgia , Falso Aneurisma/diagnóstico por imagem , Falso Aneurisma/etiologia , Falso Aneurisma/cirurgia , Humanos , Stents , Resultado do TratamentoRESUMO
Genetic variations in cytochrome P450 1A2 (CYP1A2) are associated with interindividual variability in the metabolism and efficacy of many medications. Twenty CYP1A2 variants harboring amino acid substitutions were analyzed for functional changes in enzymatic activity. Recombinant CYP1A2 variant proteins were heterologously expressed in COS-7 cells. Enzyme kinetic analyses were performed with two representative CYP1A2 substrates, phenacetin and 7-ethoxyresorufin. Among the 20 CYP1A2 allelic variants, CYP1A2*4, CYP1A2*6, CYP1A2*8, CYP1A2*15, CYP1A2*16, and CYP1A2*21 were inactive toward both substrates. CYP1A2*11 showed markedly reduced activity, but the changes in Km were different between the substrates. CYP1A2*14 and CYP1A2*20 exhibited increased activity compared to the wild-type enzyme, CYP1A2*1. This comprehensive in vitro assessment provided insight into the specific metabolic activities of CYP1A2 proteins encoded by variant alleles, which may to be valuable when interpreting the results of in vivo studies.
Assuntos
Alelos , Citocromo P-450 CYP1A2/genética , Polimorfismo Genético , Substituição de Aminoácidos , Animais , Western Blotting , Células COS , Chlorocebus aethiops , Humanos , Oxazinas/metabolismo , Fenacetina/metabolismo , Especificidade por Substrato , TransfecçãoRESUMO
Genetic variations in cytochrome P450 4A11 (CYP4A11) contributes to inter-individual variability in the metabolism of fatty acids such as arachidonic acid. CYP4A11 metabolizes arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), which is important for the regulation of blood pressure. Polymorphisms in CYP4A11 are associated with susceptibility to hypertension. In this study, we evaluated the in vitro ω-hydroxylation of arachidonic acid by 10 CYP4A11 allelic variants, which cause amino acid substitutions in the encoded proteins. CYP4A11 variants were heterologously expressed in COS-7 cells and the kinetic parameters of arachidonic acid ω-hydroxylation were estimated. Among 10 CYP4A11 variants, 5 (CYP4A11-v1, CYP4A11-v2, CYP4A11-v3, CYP4A11-v4, and CYP4A11-v7) showed no or markedly lower activity compared to wild-type CYP4A11. This functional analysis of CYP4A11 variants could provide useful information for the effective prevention and treatment of hypertension.
