Differential inhibition of human placental monooxygenase activity: evidence for multiple forms of 7-ethoxycoumarin O-deethylase

The oxidative metabolism of 2,5-diphenyloxazole (PPO) is associated with 3-methylcholanthrene inducible cytochrome P-450. The major metabolite formed has m/z of 237, corresponding to hydroxylated PPO. All the possible hydroxylated metabolites of PPO were synthesized and characterized, enabling the assignment of a structure for the major metabolite and two minor metabolites. The metabolites are easily extracted and their fluorescence is quantifiable in alkaline medium with a sample fluorescence to blank fluorescence ratio of 400:1. A sensitive HPLC assay of PPO metabolism was also developed. PPO metabolism is readily catalyzed by 3-methylcholanthrene-induced rat liver microsomes and strongly inhibited by alpha-naphthoflavone, but poorly inhibited by metyrapone or SKF 525A, indicating the involvement of cytochrome P-448 or P1-450 in the metabolism of PPO. With human lymphocytes the method has proven to be a good indicator of "aryl hydrocarbon hydroxylase" (AHH) activity, correlating well with AHH assays using benzo(alpha)pyrene (BP) as a substrate. Both the induced BP and PPO metabolism by human lymphocytes is inhibited by alpha-naphthoflavone, but not by metyrapone.

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“…1975;Ahokas 1976;Kaelin & Cummings 1984;Mutch el al. 1975;Ahokas 1976;Kaelin & Cummings 1984;Mutch el al.…”

mentioning

confidence: 99%

“…This has resulted in the use of alternative substrates by a number of groups (Cantrell et a]. 1975;Ahokas 1976;Kaelin & Cummings 1984;Mutch el al. 1984).…”

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confidence: 99%

The Metabolism of 2,5‐Diphenyloxazole (PPO) in Human Lymphocytes and Rat Liver Microsomes

Ahokas¹,

Davies²,

Jacobsen³

et al. 1987

Pharmacology & Toxicology

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“…Cigarette smoke increases AHH to a variable extent depending on the stage of pregnancy and the AHH activity is highest at term [36,38,39]. Once established, the AHH levels seem to persist for some weeks after removing the inducing stimulus [35]. In contrast to hepatic microsomes, placental microsomes with high AHH activity do not contain increased concentrations of the components for electron transport When compared to other human tissues, placenta responds sensitively to cigarette smoking [41,421.…”

Section: B Aryl Hydrocarbon Hydroxylase Activity and The Metabolism mentioning

confidence: 98%

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

Pelkonen

1989

Drug Metabolism Reviews

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“…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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Differential inhibition of human placental monooxygenase activity: evidence for multiple forms of 7-ethoxycoumarin O-deethylase

Cited by 16 publications

References 16 publications

The Metabolism of 2,5‐Diphenyloxazole (PPO) in Human Lymphocytes and Rat Liver Microsomes

The Metabolism of 2,5‐Diphenyloxazole (PPO) in Human Lymphocytes and Rat Liver Microsomes

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

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

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