Assuntos
Qualidade de Produtos para o Consumidor/normas , Contaminação de Alimentos/análise , Alimentos/normas , Substâncias Perigosas/efeitos adversos , Suplementos Nutricionais/análise , Suplementos Nutricionais/normas , União Europeia , Alimentos/efeitos adversos , Aditivos Alimentares/análise , Aditivos Alimentares/normas , Contaminação de Alimentos/prevenção & controle , Guias como Assunto , Substâncias Perigosas/análise , Humanos , Micronutrientes/normas , Nível de Efeito Adverso não Observado , Medição de Risco/métodos , Medição de Risco/normas , Gestão de RiscosRESUMO
The expression of individual xenobiotic-metabolizing cytochrome P450 (CYP) genes in human placenta was studied at the mRNA level by reverse transcriptase-polymerase chain reaction (RT-PCR). mRNAs of CYP1A1, CYP2E1, CYP2F1, CYP3A3/4, CYP3A5, and CYP4B1 were detected by RT-PCR, and CYP1A2, CYP2A6/7, CYP2B6/7, CYp2C8-19, CYP2D6, and CYp3A7 were not detected. Several enzyme activity assays and immunoblasts were used to further characterize expression of forms producing detectable mRNA transcripts. The catalytic activities of 7-ethoxycoumarin O-deethylase (ECOD), 7-ethoxyresorufin O-deethylase (EROD) and aryl hydrocarbon hydroxylase (AHH) were substantially increased in response to maternal cigarette smoking, and paralleled the amount of CYP1A1 mRNA and protein. Aromatase activities were slightly lower in placentas exposed to cigarette smoke compared with nonexposed placentas. These data show that several xenobiotic-metabolizing CYP genes are expressed in human placenta at a low level. The significant of such low-level expression is unknown, but it may have local physiological or toxic consequences.
Assuntos
Sistema Enzimático do Citocromo P-450/biossíntese , Expressão Gênica , Microssomos/enzimologia , Placenta/enzimologia , Xenobióticos/metabolismo , O-Dealquilase 7-Alcoxicumarina/metabolismo , Aromatase/metabolismo , Hidrocarboneto de Aril Hidroxilases/metabolismo , Sequência de Bases , Citocromo P-450 CYP1A1 , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Primers do DNA , DNA Complementar , Feminino , Humanos , Dados de Sequência Molecular , Oligonucleotídeos Antissenso , Oxirredutases/metabolismo , Reação em Cadeia da Polimerase , Gravidez , RNA Mensageiro/biossíntese , Fumar , Transcrição GênicaRESUMO
Drugs whose principal metabolic pathways are under polymorphic genetic regulation may show considerable interindividual pharmacokinetic variability. This could lead to clinically significant differences in the pharmacological responses of some patients and so might lead the pharmaceutical industry to stop development of the drug. This can be prevented and there are several measures that can be taken to avoid such premature termination of development. They include studies in vitro with human liver samples, and clinical pharmacological experiments designed specifically to examine possible genetic polymorphism in the disposition of the drug.