Fetal and Neonatal Development of the Microsomal Monooxygenase System

Ce, Short; Kinden, Darrell A.; Stith, Rex D.

doi:10.3109/03602537608995838

Cited by 86 publications

(36 citation statements)

References 88 publications

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“…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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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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“…Maximum induction increased concomitantly with hepatocyte differentiation, reaching adult levels of induction by 7 DI. Generally, mammals have very low levels of MFO activity during fetal development (17)(18)(19). However, AHHase and other MFO activities have been detected in human fetal tissues as early as the first trimester (20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

Development of basal and induced aryl hydrocarbon (benzo[a]pyrene) hydroxylase activity in the chicken embryo in ovo.

Hamilton

Denison

Bloom

1983

Proc. Natl. Acad. Sci. U.S.A.

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The development of the hepatic microsomal mixed-function oxidase system was studied to determine the basal level of embryonic enzyme activity and the inducibility of this system throughout growth and differentiation. Chicken embryo livers were assayed for basal and inducible hepatic aryl hydrocarbon hydroxylase (AHHase; designated elsewhere as AHH) activity from the first appearance of the liver as a discrete organ at 5 days of incubation (DI) through day 10 after hatching. In addition, wholeembryo and viscera preparations were assayed at 3 and 4 DI. Basal AHHase activity was equal to or greater than adult levels from 3 DI through hatching in all preparations (approximately 0.3-0.5 nmol/min per mg). A 3-fold increase in basal activity above adult values occurred at hatching. The onset of inducibility in chicken embryo liver between 5 and 6 DI was concomitant with hepatocyte differentiation. A developmental profile of 24-hr 3,4,3',4'-tetrachlorobiphenyl-induced AHHase activity showed 15-to 30-fold induction over controls from 7 DI through day 10 after hatching, with a maxmum of 15 nmol/min per mg at 14 DI and day 1 after hatching, a specific activity >50% greater than maximal induction in the adult. Embryonic AHHase activity was also induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin, 3-methylcholanthrene, 3-naphthoflavone, and sodium phenobarbital. Induction kinetics throughout embryonic development were similar to those reported for the adult chicken and other animals. These findings demonstrate development of a mixed-function oxidase system in very early embryogenesis and then in the liver as it differentiates. Liver AHHase activity is inducible throughout development and perinatally but such activity is under strict developmental regulation. The chicken embryo has adult levels of AHHase activity which would be sufficient to achieve metabolic activation of promutagens /carcinogens before and after hepatocyte differentiation.The chicken embryo is a sensitive indicator of the teratogenic (1) and mutagenic (2) capacity of xenobiotics. Since its development as the first in vivo sister chromatid exchange (SCE) assay (3), it has been used to screen more than 50 compounds for mutagenic activity, including both direct-and indirect-acting compounds (4, 5). The induction of SCEs at 3 days of incubation (DI) by compounds known to require activation to mutagenic metabolites indicates the presence of a xenobiotic-metabolizing system very early in chicken embryo development (4, 5). Furthermore, there was an increase in the frequency of SCEs at 6 DI from the same dose of an indirect-acting mutagen/carcinogen compared to the SCE frequency at 3 DI, in spite of a 17-fold increase in embryo weight, whereas the same dose of direct-acting mutagen at 6 DI as at 3 DI caused a decrease in SCEs in the older embryo (6). This differential response between 3 DI and 6 DI potentially could be explained by either an increase in basal enzyme levels or an increased inducibility of xenobiotic-metabolizing enzymes.Drummond et aL (7) report...

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“…Differences in body composition and immaturity of drug elimination pathways are largely responsible for these changes in disposition. In the full term neonate plasma proteins are qualitatively and quantitatively different to the adult (Wallace, 1977), water constitutes a greater proportion of body weight (Friis-Hansen, 1961;Maclaurin, 1966) and both glomerular filtration and liver metabolism are reduced (Aperia et al, 1981;Short et al, 1976). The major consequence of these differences is that drugs are generally eliminated more slowly in the neonate compared to the adult.…”

Section: Introduction Methodsmentioning

confidence: 99%

Atenolol elimination in the neonate.

Rubin¹,

Butters²,

Reynolds³

et al. 1983

Brit J Clinical Pharma

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1 The elimination of the cardioselective ,8-adrenoceptor antagonist atenolol has been studied in 35neonates by measuring drug concentration in cord blood and in blood obtained at 24 h by heel stab. 2 Elimination rate was assessed by calculating the slopes of lines joining these two concentration points. 3 The slopes had a mean of 0.043 h-1(equivalent to a half-life of 16 h) and were normally distributed with 95% of values being in the range 0.02-0.066. 4 There was no relationship between slope and neonatal weight or skinfold thickness, but most babies were at term and the range of these indices was narrow. 5 Babies who developed a bradycardia had cord atenolol concentrations and slopes which did not differ significantly from those in babies without bradycardia. 6 We conclude that atenolol elimination in the neonate is reduced when compared to adults. This prolonged elimination is consistent with the physiological characteristics of this age group and with previous observations on drugs eliminated by renal excretion.

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Fetal and Neonatal Development of the Microsomal Monooxygenase System

Cited by 86 publications

References 88 publications

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

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

Development of basal and induced aryl hydrocarbon (benzo[a]pyrene) hydroxylase activity in the chicken embryo in ovo.

Atenolol elimination in the neonate.

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