Significance of cytochrome P-450 (P-450 HFLa) of human fetal livers in the steroid and drug oxidations

Kitada, Munehiro; Kamataki, Tetsuya; Itahashi, Koshiro; Rikihisa, Tadaaki; Kanakubo, Yoshio

doi:10.1016/0006-2952(87)90350-9

Cited by 74 publications

(25 citation statements)

References 22 publications

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“…These observations suggest that steroid hormones and their receptors play a role in the regulation of CYP3A7. The time course of increase in endometrial and placenta CYP3A7 protein and mRNA during pregnancy coincides with an increase in systemic levels of DHEA-s (12), a known substrate for CYP3A7 (21,23). Substrate mediated induction of CYP3A7 through DHEA-s bound to its receptor (58) could account for the increased placental and endometrial CYP3A7 mRNA and protein we have found during pregnancy.…”

Section: Discussionmentioning

confidence: 69%

“…CYP3A7 was previously thought to be expressed only in fetal liver during early pregnancy (24,25), perhaps to protect the fetus from DHEA-s toxicity (23). When fetal adrenals are stimulated by ACTH in the second trimester, synthesis of DHEA-s increases.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the 16-a-hydroxylated form of DHEA-s does not inhibit progesterone biosynthesis ( 17) and may be less toxic to the fetus. Recently, a form of cytochrome P450 termed HFLa (CYP3A7) that has been thought to be expressed in fetal liver exclusively (18)(19)(20)(21)(22)(23)(24)(25) was found to catalyze 16-a-hydroxylation of DHEA-s (23). One interpretation of this finding might be that 16-a-hydroxylation of DHEA-s serves a self protective fetal function confined to the developing liver.…”

Section: Introductionmentioning

confidence: 99%

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Identification of the fetal liver cytochrome CYP3A7 in human endometrium and placenta.

Schuetz¹,

Kauma²,

Guzelian³

1993

J. Clin. Invest.

104

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Placenta and endometrium carry out steroidogenic biotransformation reactions such as 6-ft-hydroxylation of cortisol, a reaction characteristic of the dominant family of cytochromes P450 in human liver, CYP3A. To investigate the possible role in these extrahepatic tissues of the CYP3A microsomal hemoproteins, we analyzed placental and endometrial microsomes on Western blots developed with an anti-human CYP3A antibody. We found an immunoreactive 51,500 D protein that migrated between CYP3A3 (HLp) and CYP3A5 (HLp2) identical with CYP3A7 (HFLa). CYP3A7, a form found prominently in human fetal liver microsomes, was first isolated as a liver 16-adehydroepiandrosterone-sulfate hydroxylase. Northern blot analysis of total RNA isolated from placenta or from endometrium demonstrated a single band that cross-hybridized with a CYP3A7 cDNA. Amplification of the same RNA samples with the use of primers specific for CYP3A7, produced a 552-bp segment that had the predicted size and the same DNA sequence as does liver CYP3A7 cDNA. Hybridizable endometrial CYP3A7 mRNA was detected more frequently (six of seven samples) and in higher amounts (-12-fold higher) in pregnant compared with nonpregnant women (4 of 12 samples). In addition, during the secretory phase of the menstrual cycle CYP3A7 expression was sixfold higher than in the one sample from the proliferative phase that had detectable CYP3A7 mRNA. Moreover, the amounts of placental and endometrial CYP3A7 mRNA and protein increased substantially from the first to the second trimester of pregnancy. We conclude that placenta and endometrium express the same P450 as is found in fetal liver. These tissues represent a previously unrecognized and quantitatively important site for 6-ft-hydroxylation and 16-a-hydroxylation of specific steroid precursors, possibly for protection of the fetus from the toxic effects of endogenous steroids and foreign substrates. (J. Clin. Invest. 1993.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Identification of the fetal liver cytochrome CYP3A7 in human endometrium and placenta.

Schuetz¹,

Kauma²,

Guzelian³

1993

J. Clin. Invest.

104

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“…This suggests that caffeine metabolism may depend in the foetus on the major foetal liver cytochrome, CYP3A [14,[20][21][22][23]. The C-8-hydroxylation of caffeine may also be mediated by CYP3A.…”

Section: Discussionmentioning

confidence: 99%

Biotransformation of caffeine in human liver microsomes from foetuses, neonates, infants and adults.

Cazeneuve

Pons

Rey

et al. 1994

Brit J Clinical Pharma

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1 Caffeine metabolism was studied in human liver microsomes from foetuses (n = 10), neonates (n = 10), infants (n = 9) and adults (n = 5). Caffeine and its metabolites, 1-3-7-trimethyluric acid, paraxanthine, theophylline and theobromine, were assayed by h.p.l.c. Methoxyresorufin-O-demethylase activity (MEROD) was determined and immunoquantifiable levels of CYP1A2 were measured.2 The formation of the dimethylxanthines by N-3, N-7 or N-i-demethylation was significantly less in foetuses, neonates and infants than in adults, as shown previously in vivo. The formation of 1-3-7-trimethyluric acid (C-8-hydroxylation) was not significantly different between age groups. The production of total dimethylxanthines, paraxanthine and theophylline increased significantly with age within the neonate-infant group over at least the 0-300 day range (rs = 0.739, 0.667, 0.682, respectively). These data differ from those reported in vivo which suggested that N-3 and N-7-demethylations matured at about 120 days. The difference in maturational profiles of each metabolic pathway suggests that the reactions depend on different isoenzymes. The delay in the maturation of N-1 compared with N-3 and N-7-demethylation is in agreement with previous in vivo data. 3 In the neonate-infant group, only N-3-demethylation correlated with both MEROD activity (rs = 0.681; P < 0.05) and CYP1A2 microsomal concentration (r, = 0.454; P = 0.05), suggesting that, as in adults, this reaction depends on CYP1A2. 4 In the foetal samples, the production of total dimethylxanthines, paraxanthine and theobromine decreased significantly (rs = -0.879, -0.767, -0.708, respectively) with increasing gestational age. Only CYP3A has previously been detected in human foetal liver; neither CYPlAl nor CYP1A2 were present, suggesting that the metabolic pathways of caffeine depend on CYP3A at this stage of development.

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“…Thus, properties of P-450HFLa were further studied. Upon incubation of the reconstituted system, this cytochrome P-450 catalyzed the oxidation of a variety of substrates including drugs and steroids (Kitada et al 1987a). Dehydroepiandrosterone 3-sulfate (RHEA-S) was also oxidized by this cytochrome at 16a-position (Kitada et al 1987b).…”

Section: Properties Of P-450hflamentioning

confidence: 99%

Human Fetal Liver Cytochrome P-450. Capacity to Form Genotoxic Metabolites.

Kamataki

Kitada

Komori

et al. 1992

Tohoku J. Exp. Med.

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Significance of cytochrome P-450 (P-450 HFLa) of human fetal livers in the steroid and drug oxidations

Cited by 74 publications

References 22 publications

Identification of the fetal liver cytochrome CYP3A7 in human endometrium and placenta.

Identification of the fetal liver cytochrome CYP3A7 in human endometrium and placenta.

Biotransformation of caffeine in human liver microsomes from foetuses, neonates, infants and adults.

Human Fetal Liver Cytochrome P-450. Capacity to Form Genotoxic Metabolites.

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