Human Placental Xenobiotic and Steroid Biotransformations Catalyzed By Cytochrome P450, Epoxide Hydrolase, and Glutathione S-Transferase Activities and Their Relationships to Maternal Cigarette Smoking

Pasanen, Markku; Pelkonen, Olavi

doi:10.3109/03602538909030305

Cited by 33 publications

(9 citation statements)

References 178 publications

(62 reference statements)

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“…Although seeds for the projects on the expression and regulation of CYP enzymes in human tissues were sown during our early studies on AHH and COH activities in mouse liver and in human tissues, the full fruits were reaped under the supervision and leadership of my younger colleagues (such as Kirsi Vähäkangas, Hannu Raunio, Arja Rautio, Markku Pasanen, Jukka Hakkola with the help of many PhD students) and my role was effectively that of an ‘elderly statesman’. Highlights from this period between the late 1980s and the first decade of the second millennium include the following projects: development of assays to measure steroid‐synthesizing and drug‐metabolizing enzymes in human placenta and other tissues and the application of these methods to study environmental influences , elucidation of xenobiotic metabolism in human lung preparations and in lung‐derived permanent cell lines , and multiple transcriptional factors and signalling pathways involved in the regulation of cyp2a5 in mouse hepatocytes .…”

Section: Expression and Regulation Of Cyp Enzymesmentioning

confidence: 99%

Drug Metabolism – From In Vitro to In Vivo, From Simple to Complex

Pelkonen

2015

Basic Clin Pharma Tox

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Drug metabolism is the crucial part of pharmaco-and toxicokinetics and consequently is associated with both desirable and adverse effects of most xenobiotics, compounds foreign to the body. This minireview follows some advances of the field over the last 50 years or so through the experiences and work of one scientist. Thus, this minireview represents a rather personal view of research in one research field. Drug metabolism is affected and controlled by a huge number of factors and conditions such as individual development, species differences, drug-drug interactions and various environmental, host and genetic factors working via a variable set of regulatory mechanisms. All these different factors create wide individual, population and species variability with obvious repercussions to clinical drug therapy and chemical risk assessment. This minireview also provides glimpses to methodological developments over recent decades and ends up presenting a few promising approaches and techniques such as various omics and high-content and high-throughput techniques feeding huge amounts of data to computational integration and modelling, which constitute the basis for systems or network pharmacology and toxicology.

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Section: Expression and Regulation Of Cyp Enzymesmentioning

confidence: 99%

Drug Metabolism – From In Vitro to In Vivo, From Simple to Complex

Pelkonen

2015

Basic Clin Pharma Tox

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“…Muitas drogas são transportadas através da placenta por difusão simples, sem gasto de energia, dependente do gradiente de concentração da droga livre, da razão e da extensão da barreira placentária de troca 34 . A inacessibilidade à placenta in situ e os conceitos sobre a segurança de uso de drogas para a mãe e o feto têm restringido os estudos diretos em placenta humana.…”

Section: Anestésicosunclassified

Transferência placentária de drogas

Cavalli¹,

Baraldi²,

Cunha³

2006

Rev. Bras. Ginecol. Obstet.

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ResumoGrávidas podem depender do uso de medicações para minimizar os agravos da doença preexistente. A gravidez, por si só, pode causar situações que comprometem o bem-estar materno, como náuseas e vômitos, as quais necessitam de tratamento. O obstetra deve estar atento à transferência placentária de drogas e à exposição do feto a agentes teratogênicos ou tóxicos, que podem comprometer o seu desenvolvimento ou mesmo sua vida futura.O transporte através da placenta envolve o movimento de moléculas entre três compartimentos: sangue materno, citoplasma do sinciciotrofoblasto e sangue fetal. Esse movimento pode ocorrer pelos seguintes mecanismos: difusão simples, difusão facilitada, transporte ativo, bombas classe P, V, F e grande família ABC e endocitose. Com o uso de anticonvulsivantes a incidência de malformações maiores em recém-nascidos expostos é de 4 a 6%, comparado com 2 a 4% na população geral. A politerapia é mais lesiva, especialmente se o ácido valpróico e a hidantoína fazem parte da associação. Para as pacientes epilépticas clinicamente assintomáticas há dois anos recomenda-se a suspensão da drogas em uso, porém se apresentam crises, torna-se prudente consultar neurologista para discussão da terapia anticonvulsivante com melhores benefícios e menores efeitos colaterais. Os anestésicos locais e os opióides são largamente utilizados durante a resolução da gestação. A lidocaína utilizada como anestésico por via perineal para episiotomia, na dose fi xa de 400 mg, apresenta alta concentração plasmática materna e alta taxa de transferência placentária no momento do nascimento, que vem alertar para o cuidado no uso de doses repetidas. A bupivacaína administrada por via epidural representa anestésico seguro, apresentando-se na forma racêmica e com transferência placentária em torno de 30%. A fentanila, anestésico opióide, utilizado por via epidural na resolução por cesariana, na dose fi xa de 0,10 mg, apresenta alta taxa de transferência placentária, da ordem de 90%, o que vem alertar para cautela no uso de doses repetidas em analgesia durante o trabalho de parto. PALAVRA-CHAVES:Troca materno-fetal; Anormalidades induzidas por drogas; Gravidez, Anticonvulsivos/efeitos adversos; Anestésicos/efeitos adversos Abstract Pregnant women may depend on the use of medications to minimize the problems caused by preexisting disease, and pregnancy itself can cause situations that compromise the maternal well-being and that require treatment. The obstetrician should be aware of the placental transfer of drugs and of fetal exposure to teratogenic or toxic agents that might compromise the development of the fetus or even its future life.Transport through the placenta involves the movement of molecules between three compartments: maternal blood, cytoplasm of the syncytiotrophoblast, and fetal blood. This movement can occur through the following mechanisms: simple diffusion, facilitated diffusion, active transport, class P, V, F and large ABC family pumps, and endocytosis. With the use of anticonvulsants the incidence of major m...

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“…GST is a multifunctional enzyme system catalyzing the conjugation of biologically active electrophiles to endoge Gynecol Obstct Invest 1996:42:154-158nous glutathione [1,24], GST activity has been identified in the cytosol of human placenta and appears to be pri marily located in the chorionic villi and to a lesser extent in the amnion [25]. GST is active early in pregnancy and may play a crucial role in the protection of the fetus against electrophiles or other cell-damaging compounds [24] such as those produced by cytochrome P450 1A 1.…”

Section: Discussionmentioning

confidence: 99%

“…Studies of placental tissue homogenates and subfrac tions have shown that several of the known drug-metabo lizing enzyme systems are present in the placenta, al though at considerably lower activities than in the liver [1][2][3][4], For example, P450 1A1 activity, which can convert the polycyclic aromatic hydrocarbons in cigarette smoke to reactive metabolites, has been observed in the placenta and, interestingly, is induced by cigarette smoke [5,6]. The placenta, via cytochrome P450 19A1 (aromatase), is also a major source of estrogens during pregnancy [7,8].…”

Section: Introductionmentioning

confidence: 99%

Regiospecificity of Placental Metabolism by Cytochromes P450 and Glutathione S-Transferase

McRobie

Glover²,

Tracy³

1996

Gynecol Obstet Invest

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The placenta possesses the ability to metabolize numerous xenobiotics and endogenous steroids. However, it is unknown whether regional differences in these enzymatic reactions exist in the human placenta. To this end, we undertook a study of four regions of the placenta, the chorionic plate, maternal surface, placental margin and whole tissue, to assess the activities of cytochrome P450 1A1 and 19A1 (aromatase) and glutathione S-stransferase in these fractions. No differences in either P450 1 A1 or glutathione S-transferase activities were noted among any of the placental fractions. However, with respect to P450 19A1 activity, the placental margin differed significantly from all other fractions (p < 0.05). This study demonstrates that whole tissue samples of the human placenta are adequate for placental cytochrome P450 and glutathione S-transferase metabolism studies.

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Human Placental Xenobiotic and Steroid Biotransformations Catalyzed By Cytochrome P450, Epoxide Hydrolase, and Glutathione S-Transferase Activities and Their Relationships to Maternal Cigarette Smoking

Cited by 33 publications

References 178 publications

Drug Metabolism – From In Vitro to In Vivo, From Simple to Complex

Drug Metabolism – From In Vitro to In Vivo, From Simple to Complex

Transferência placentária de drogas

Regiospecificity of Placental Metabolism by Cytochromes P450 and Glutathione S-Transferase

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