Immunochemical and molecular biological studies on human placental cigarette smoke-inducible cytochrome P-450-dependent monooxygenase activities

Pasanen, Markku; Haaparanta, Tapio; Sundin, Maria; Sivonen, Päivi; Vakakangas, Kirsi; Raunio, Hannu; Hines, Ronald N.; Gustafsson, J; Pelkonen, Olavi

doi:10.1016/0300-483x(90)90108-s

Cited by 48 publications

(14 citation statements)

References 21 publications

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“…The determined EFC O-deethylase activity in placental subcellular fractions revealed a wide range of values for V max (Table 1) and was arbitrarily divided into two groups: low activity, Ͻ 40pmol/mg protein ⅐ min, and the remainder as high activity. A similar observation for O-deethylase activity was reported earlier; the high activity group of placentas was associated with maternal smoking during pregnancy and has been attributed to induction of CYP 1A1 (Pasanen et al, 1990). On the other hand, the activity of our placental preparations in the N-dealkylation of BUP did not reflect the wide range of variability observed for the O-deethylation of EFC (Table 1).…”

Section: Discussionsupporting

confidence: 88%

“…Accordingly, the oxygenase activity of placental subcellular fractions was determined by utilizing the EFC O-deethylation to the fluorescent product HFC (DeLuca et al, 1988;Buters et al, 1993). Two distinct forms of monooxygenases catalyze this reaction in placental tissue; namely, a constitutive form that includes CYP 19/aromatase (Meigs, 1987) and an inducible CYP 1A1 (Pasanen et al, 1990). The determined EFC O-deethylase activity in placental subcellular fractions revealed a wide range of values for V max (Table 1) and was arbitrarily divided into two groups: low activity, Ͻ 40pmol/mg protein ⅐ min, and the remainder as high activity.…”

Section: Discussionmentioning

confidence: 99%

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Aromatase Is the Major Enzyme Metabolizing Buprenorphine in Human Placenta

Deshmukh

Nanovskaya²,

Ahmed³

2003

J Pharmacol Exp Ther

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Buprenorphine (BUP) is a partial opiate agonist used for treatment of the adult and the pregnant addicted to this class of narcotics. The kinetic parameters for transplacental transfer and the metabolism of BUP during its perfusion in a placental lobule were the subject of an earlier report from our laboratory. The aim of this investigation is to identify and characterize the enzyme catalyzing the metabolism of BUP in term human placenta. Norbuprenorphine (norBUP) is the only metabolite formed as determined by high performance liquid chromatography and mass spectrometry. The activity of the enzyme responsible for BUP metabolism is highest in the microsomal fraction and lowest in the cytosolic, with the mitochondrial in between. Compounds with selective affinity to the enzyme aromatase (CYP 19), namely 4-hydroxyandrostenedione and aminoglutethimide, caused Ͼ70% inhibition of norBUP formation. Monoclonal antibodies raised against CYP 19 were the most potent inhibitors of BUP dealkylation. A comparison between the data obtained from the saturation isotherm for BUP dealkylation by placental microsomes and a commercially available system of cDNA-expressed CYP 19 indicated similar kinetic parameters, with apparent K m values of 12 Ϯ 4.0 and 14 Ϯ 8.0 M, respectively. Therefore, aromatase is the major enzyme catalyzing the biotransformation of BUP to norBUP in term human placentas obtained from healthy pregnancies. The minor involvement of other cytochrome P450 isoforms or enzyme(s) in the metabolism of BUP in placental tissue cannot be ruled out.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Aromatase Is the Major Enzyme Metabolizing Buprenorphine in Human Placenta

Deshmukh

Nanovskaya²,

Ahmed³

2003

J Pharmacol Exp Ther

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“…For example, it has been reported that a placental cytochrome P450 is responsible for the hydroxylation of benzo[a]pyrene via aryl hydrocarbon hydroxylase (AHH). Previous studies on AHH activity have demonstrated higher levels of this activity in placentas of smokers but not in those of nonsmokers [19,25]. Pasanen et al [26] indicated that P450 1A1 is probably responsible for cigarette-smoke induced activity.…”

Section: Discussionmentioning

confidence: 97%

“…Numerous studies on the development of the drug-metabolizing system in fetuses and placentas have been published [22][23][24][25]. For example, it has been reported that a placental cytochrome P450 is responsible for the hydroxylation of benzo[a]pyrene via aryl hydrocarbon hydroxylase (AHH).…”

Section: Discussionmentioning

confidence: 99%

Aromatase and Estrogen 2-Hydroxylase Activities of Human Placental Microsomes in Pregnancy-Induced Hypertension.

et al. 1996

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Abstract. 2-Hydroxylationis one of the major metabolic pathways of estrogens and is believed to be catalyzed by a form of cytochrome P450. Recently it has been reported that estrogen 2-hydroxylase activity in human placenta is catalyzed by aromatase.Some investigators suggested the effect of catechol estrogen on human placental steroidogenesis which may be related to pregnancy-induced hypertension (PIH) through the inhibition of catechol-0-methyltransferase (COMT) activity. In order to better understand the interrelationship between placental aromatase and estrogen 2-hydroxylase activities in PIH patients, both activities were evaluated in the PIH placentas.Human placental microsomes obtained from PIH patients were incubated with [1/3-3H]androstenedione or [2-3H]estradiol in the presence of NADPH. Aromatase and estrogen 2-hydroxylase activities were assessed by the tritium water method. The immunosuppression patterns of both activities due to monoclonal antiaromatase cytochrome P450 antibody (MAb3-2C2) were studied. Estrogen 2-hydroxylase activity was significantly higher in PIH placentas (4.7 ± 0.9 pmol/min/mg protein, n=7) than in normal placentas (3.0 ± 0.7 pmol/min/mg protein, n=7). When the PIH placental microsomes were subjected to immunosuppression by 1 to 100 µg IgG of MAb3-2C2, estrogen 2-hydroxylase activity was suppressed by 94 to 65% whereas aromatase activity was strongly suppressed by 72 to 17%, respectively. From our results of high estrogen 2-hydroxylase activity in PIH placentas, it is assumed that there is a different estrogen catalyzing mechanism in PIH placentas.

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“…This elevated enzyme activity is likely due to the induction of CYP1A1 by smoking because the placentas were from women of similar ages. It is well-established that smoking can induce placental CYP1A1 at the mRNA level (27)(28)(29)(30)(31) and at protein and enzyme activity level (32)(33)(34)(35)(36)(37).…”

Section: Effects Of Smokingmentioning

confidence: 99%

In vitro Characterization of the Oxidation of a Pyridinium Metabolite of Haloperidol by Human Placenta: The Effect of Smoking

Fang

Song

2012

J Pharm Pharm Sci

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-Purpose. The antipsychotic drug haloperidol can be metabolised to pyridinium metabolites haloperidol pyridinium (HP + ) and reduced haloperidol pyridinium (RHP + ). These pyridinium metabolites were proposed to contribute to the extrapyramidal side effects of haloperidol, because they are structural analogues of N-methyl-4-phenylpyridinium (MPP + ), a well-known neurotoxin. RHP + can be oxidized to HP + by CYP1A1. In the current study, the oxidation of RHP + to HP + was investigated using human placenta microsomal preparations which contain relatively high levels of CYP1A1. Methods. Cytochrome P450 isoenzymes responsible for the metabolism of RHP + were characterized in vitro using human placenta microsomal preparations from smokers and non-smokers. Results. A comparison of the metabolic activities between smokers and non-smokers suggests that smokers had higher activities for the oxidation of RHP + . A selective antibody against CYP1A1 was a partial inhibitor of RHP + oxidase in placenta from smokers but had no effect in placenta from non-smokers. Furafylline and ketokonazole were shown to be stronger inhibitors of the oxidation of RHP + to HP + in liver than in placenta. This seems to indicate important contributions of CYP1A1 and CYP3A7 as compared to CYP1A2 and CYP3A4, respectively, because furafylline and ketokonazole are stronger inhibitors of CYP1A2 and CYP3A4 than CYP1A1 and CYP3A7, respectively. Interestingly, α-naphathoflavone enhanced the metabolic activity in liver microsomes due to its activator effect on CYP3A4. On the other hand, α-naphathoflavone partially inhibited the activity in placenta microsomes, indicating a role played by CYP1A1 or CYP1A2 in the oxidation of RHP + in placenta. Conclusions. These data indicate that CYP1A1 plays an important role in the oxidation of RHP + to HP + in placenta from smokers. CYP3A7 and CYP3A4 could also play important roles in the metabolism of RHP + in placenta microsomes.

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Immunochemical and molecular biological studies on human placental cigarette smoke-inducible cytochrome P-450-dependent monooxygenase activities

Cited by 48 publications

References 21 publications

Aromatase Is the Major Enzyme Metabolizing Buprenorphine in Human Placenta

Aromatase Is the Major Enzyme Metabolizing Buprenorphine in Human Placenta

Aromatase and Estrogen 2-Hydroxylase Activities of Human Placental Microsomes in Pregnancy-Induced Hypertension.

In vitro Characterization of the Oxidation of a Pyridinium Metabolite of Haloperidol by Human Placenta: The Effect of Smoking

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