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

Abstract

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.

Simultaneous determination of 1-chloro-2,4-dinitrobenzene, 2,4-dinitrophenyl-S-glutathione and its metabolites for human placental disposition studies by high-performance liquid chromatography

“…Human placental glutathione-S-transferase isoform P1-1 (GSTP1-1) conjugates CDNB with glutathione to form 2,4-dinitrophenyl-S-glutathione (DNP-SG) [1]. DNP-SG is a known substrate of ATP-binding cassette (ABC) transporter isoforms C1 and C2 (multidrug resistance associated proteins 1 and 2) [2] and isoform G2 (breast cancer resistance protein) [3].…”

“…DNP-Cys is a precursor in the N-acetyltransferase-mediated formation of DNP-NAc as a part of the mercapturic acid pathway [8]. The activity of human placental GSTP1-1 towards CDNB metabolism has been described [1]; however the efflux mechanism for DNP-SG from human placental tissue has not been established. Furthermore, formation of secondary metabolites of DNP-SG might be expected since ␥-glutamyl transferase [23] and N-acetyltransferase [24] activities have been detected in the human placenta.…”

Inter-Individual Variation in Levels of the Detoxifying Enzyme Glutathione S-Transferasepi(GSTP1) in Placentas from a Mexican Population

“…P450 1A1 and GST activities were similar when measured in four regions of the placenta (McRobie et al 1996). Glutathione, cysteine, and GST enzyme levels, and activities at twelve different standardized positions in six placentas from healthy, uncomplicated vaginal deliveries were similar, except for GSTA1 and A2 (Raijmakers et al 2002).…”

Glutathione S-Transferase in Human Endometrium: Quantitation and Interindividual Variability in Isoform Content

“…Unfortunately, the GST monoclonal antibody which was used did not yield measurable inhibition at any concentration employed (data not shown). Of significance, this antibody did not inhibit human placental GST activity which is recognized as a pure source of GST [3,4].…”

“…The variability in the isoform composition in various tissues is striking. For example, human placenta and erythrocytes appear to have only GST isoforms [3,4] while human skeletal muscle reportedly contains moderate levels of the  and Ì forms and none of the ·-isozymes [5]. Finally in terms of qualitative differences, human liver and testis are rich in GST· and have little or none of the  form [3,6].…”