Epoxide Hydrolase in Human Fetal Liver

Pacifici, Gian Maria; Rane, Anders

doi:10.1159/000137807

Cited by 23 publications

(9 citation statements)

References 8 publications

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“…The sulfotransferase activity was not de pendent on the length of storage. The large interindividual variation seems to be typical of the sulfotransferase because our previous studies on acetyl transferase [Pacifici et al, 1986], glutathione transferase [Pacifici et al, 1981[Pacifici et al, , 1987, UDP-glucuronyl transferase [Pacifici et al, 1982] and microsomal epox ide hydrolase [Pacifici and Rane, 1983] have shown that the activity of these enzymes var ies in a more narrow range. The exposure of a fetus to molecules inactivated by the sulfo transferase may thus be difficult to predict in human fetus.…”

Section: Discussionmentioning

confidence: 95%

Sulfotransferase in Humans: Development and Tissue Distribution

Pacifici¹,

Franchi

Colizzi

et al. 1988

Pharmacology

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Sulfotransferase with 2-naphthol as substrate was investigated in the cytosolic fraction of human fetal liver, lungs, kidneys, adrenal glands, intestine and placenta and also in liver, lungs, kidneys, intestinal and urinary bladder mucosa from human adult subjects. All tissue specimens assayed catalyzed the sulfation of 2-naphthol at a significant rate. The activity (expressed as pmole per minute per milligram protein; mean ± SD) was 211 ± 197 (n = 46) fetal liver; 22 ± 12 (n = 29) placenta; 625 ± 205 (n = 42) human adult liver. In fetal kidneys (576 ± 177; n = 6) and gut (558 ± 293; n = 6) the activity was twice as high as in liver. In the lungs (273 ± 125; n = 6) and in the adrenals (174 ± 119; n = 19) the sulfotransferase activity was comparable with the hepatic one. In human adult extrahepatic tissues the highest activity was found in the intestinal mucosa (153 ± 49; n = 4) and the lowest one in the urinary bladder mucosa (16 ± 4; n = 4). This paper shows that the sulfotransferase has a wide distribution in the human fetus and the distribution pattern of this enzyme is different in the human fetus and adult subject.

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Section: Discussionmentioning

confidence: 95%

Sulfotransferase in Humans: Development and Tissue Distribution

Pacifici¹,

Franchi

Colizzi

et al. 1988

Pharmacology

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“…Different forms of EH have been dem onstrated in microsomes from human adult liver [Guengerich et al, 1979a] and it is pos sible that our findings reflect the presence of different isozymes. The existence of multiple forms of EH in human fetal liver has pre viously been suggested [Pacifici and Rane, 1983a].…”

Section: Discussionmentioning

confidence: 99%

“…Our previous work has demonstrated that these two enzymatic pathways are operating in the mid-gesta tional human fetus [Pacifici andRane, 1982, 1983a;Pacifici et al. 1981Pacifici et al. , 1983a.…”

Section: Introductionmentioning

confidence: 99%

Isolation of Nuclear Fractions from Human Fetal Tissues

Pacifici¹,

Glaumann²,

Rane³

1985

Pharmacology

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The aryl hydrocarbon hydroxylase (AHH) and epoxide hydrolase (EH) activities with styrene oxide and benzo[a]pyrene-4,5-oxide as substrates were investigated and compared in the nuclear and microsomal fractions isolated from the human fetal liver, adrenals, kidneys and lungs. The purity of the fractions was estimated by electron microscopy and found to be around 85% for the nuclear and 90% for the microsomal fractions. All tissues catalyzed the hydration of the two epoxides at significant rates. The EH followed Michaelis-Menten kinetics in all fractions. The highest activities were seen in the liver and the adrenals. The nuclear/microsomal ratios of the EH activity was tissue dependent, being highest in the kidneys and lungs.

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“…In fetal liver, adrenal, kidney, and lung ranging from 16 to 25 weeks gestation, EPHX1 activity, as measured using the substrate benzo[a]pyrene-4,5-oxide, was reported as 150 pmol/min/mg protein in the liver and adrenal glands, but only 50 pmol/min/mg protein in kidney and lung (Pacifici et al, 1983b). This same group subsequently demonstrated an increase in hepatic EPHX1 catalytic activity between 10 and 25 weeks gestation, although sample-size and intersubject variability prevented the authors from suggesting anything other than a weak correlation between activity and gestational age (Pacifici and Rane, 1983). Employing an immunological approach in eight fetal livers ranging from 17 to 27 weeks gestation, Cresteil et al (1985) demonstrated EPHX1-specific content between approximately 40 and 400 pmol/mg microsomal protein whereas in four adult liver samples, the specific content ranged from 750 to 1200 pmol/mg microsomal protein.…”

Section: Epoxide Hydrolasementioning

confidence: 98%

The Ontogeny of Human Drug-Metabolizing Enzymes: Phase II Conjugation Enzymes and Regulatory Mechanisms: Table 1

McCarver¹,

Hines²

2002

J Pharmacol Exp Ther

323

151

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Changes in phase II drug-metabolizing enzyme expression during development, as well as the balance between phase I and phase II enzymes, can significantly alter the pharmacokinetics for a given drug or toxicant. Although our knowledge is incomplete, many of the phase II enzymes are expressed early in development. There is evidence for glutathione S-transferase A1/A2 (GSTA1/A2), GSTM, and GSTP1 in fetal liver, lung and kidney, although tissue-specific patterns and changes with time are observed. N-Acetyltransferase 1 (NAT1) activity also has been reported throughout gestation in fetal liver, adrenal glands, lung, kidney, and intestine. Only postnatal changes in NAT1 expression were apparent. Nothing is known about human NAT2 developmental expression. Some UDP-glucuronosyltransferase and sulfotransferase isoforms also are detectable in fetal liver and other tissues by the first or second trimester, and substantial changes in isoform expression patterns, as well as overall expression levels, are observed with increasing maturity. Finally, expression of both epoxide hydrolases 1 and 2 (EPHX1 and EPHX2) is observed in fetal liver, and for the former, increased expression with time has been documented. Less is known about ontogenic molecular control mechanisms. Limited data suggest that the hepatocyte nuclear factor and CCAAT/enhancer binding protein families are critical for fetal liver drug-metabolizing enzyme expression whereas D element binding protein and related factors may regulate postnatal hepatic expression. There is a paucity of data regarding mechanisms for the onset of extrahepatic fetal expression or specific mechanisms determining temporal switches, such as those observed within the CYP3A and flavin-containing monooxygenase families.Taking advantage of electrophilic functional groups already present on the molecule, or ones introduced during phase I metabolism, the phase II drug-metabolizing enzymes (DMEs) are characterized by their ability to conjugate xenobiotics using small molecular weight, organic donor molecules such as glutathione, UDP-glucuronic acid, or acetyl coenzyme A. These reactions generally result in pharmacological inactivation or detoxification, although instances of bioactivation are known. Conjugation products also can be substrates for specific transport enzymes, thus facilitating elimination from the body. Historically, research on DMEs has placed more emphasis on those catalyzing phase I versus phase II reactions. This also has been true with respect to studies on DME developmental expression. Given the importance of the conjugation enzymes in drug and toxicant disposition and, in particular, how the balance between phase I and phase II enzymes can dramatically alter pharmacokinetics and therefore therapeutic efficacy and/or xenobiotic toxicity, this area deserves increased attention.Advances in our understanding of phase II enzyme expression during ontogeny have been hampered by many of the same problems discussed for the phase I enzymes (Hines and McCarver, 2002). These ...

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Epoxide Hydrolase in Human Fetal Liver

Cited by 23 publications

References 8 publications

Sulfotransferase in Humans: Development and Tissue Distribution

Sulfotransferase in Humans: Development and Tissue Distribution

Isolation of Nuclear Fractions from Human Fetal Tissues

The Ontogeny of Human Drug-Metabolizing Enzymes: Phase II Conjugation Enzymes and Regulatory Mechanisms: Table 1

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