Cytosolic epoxide hydrolase in fetal and adult human liver

Pacifici, Gian Maria; Colizzi, Cesare; Giuliani, L.; Rane, Anders

doi:10.1007/bf01234486

Cited by 26 publications

(5 citation statements)

References 33 publications

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“…Using styrene oxide as a substrate, EPHX2 exhibited activities of 230 pmol/min/mg protein in the fetal liver (10 specimens at 15 to 24 weeks gestation) with an approximate 4-fold increase in the adult (14 specimens, 29 to 69 years of age) (Pacifici et al, 1983a). A subsequent study with a more sensitive assay for trans-stilbene oxide hydration demonstrated EPHX2 as early as 14 weeks in the fetal liver (Pacifici et al, 1988).…”

Section: Epoxide Hydrolasementioning

confidence: 99%

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

McCarver¹,

Hines²

2002

J Pharmacol Exp Ther

319

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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Section: Epoxide Hydrolasementioning

confidence: 99%

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

McCarver¹,

Hines²

2002

J Pharmacol Exp Ther

319

151

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“…Some phase II enzymes are already expressed at high levels since very early during gestation (e.g. epoxide hydrolase) (31). Interestingly, the glutathione‐ S ‐transferase (GST) activity is markedly reduced in spontaneous miscarriages at 28–36 weeks of gestation (32).…”

Section: Phase II Enzymesmentioning

confidence: 99%

Molecular bases of the fetal liver–placenta–maternal liver excretory pathway for cholephilic compounds

Marin

Macı́as

Briz

et al. 2008

Liver International

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Potentially toxic endogenous compounds, such as bile acids (BAs) and biliary pigments, as well as many xenobiotics, such as drugs and food components, are biotransformed and eliminated by the hepatobiliary system with the collaboration of the kidney. However, the situation is very different during pregnancy because the fetal liver produces biliary compounds despite the fact that this organ, owing to its immaturity, is not able to eliminate them into bile. Moreover, the excretory ability of the fetal kidneys is also very limited. Thus, during the intra-uterine life, the major route to eliminate fetal BAs and biliary pigments is their transfer to the mother across the placenta. The maternal liver and, to a lesser extent, the maternal kidney, are then in charge of their biotransformation and elimination into faeces and urine respectively. This review describes current knowledge of the machinery responsible for the detoxification and excretion of cholephilic compounds through the pathway formed by the fetal liver-placenta-maternal liver trio. Mechanisms of detoxification of biliary compoundsOne of the most important roles of the liver is to carry out the secretion into bile of a large variety of structurally unrelated compounds. For some of them, commonly known as cholephilic compounds, the hepatobiliary pathway is the major route for their elimination from the body. Among these substances are several endogenous anions, such as bile acids (BAs) and biliary pigments, mainly biliverdin and bilirubin. During intra-uterine life, the elimination of cholephilic organic anions (COAs) occurs through the excretory pathway constituted by the fetal liverplacenta-maternal liver trio (Fig. 1). When the last element of this trio cannot carry out its task in an efficient manner, as happens in gestations complicated by intrahepatic cholestasis of pregnancy (ICP) -a pregnancy-specific disorder that mainly occurs during the third trimester of pregnancy and is characterized primarily by pruritus, altered liver enzymes and, less frequently, jaundice, the overall excretion of these compounds is impaired and they accumulate first in the mother but then in the placenta and finally in the foetus. The elimination of some COAs is carried out without biotransformation. In these cases, only transport mechanisms of uptake (phase 0) and secretion (phase III) are involved in the detoxification process (Fig. 2) (1). In contrast, other COAs do undergo chemical modifications during their intracellular residence. These consist of oxidation/reduction reactions (phase I) and/or conjugation with polyatomic groups (phase II) (Fig. 2). The present review provides an overview of current information regarding the molecular bases and regulation of the excretory pathway formed by the fetal liver-placenta-maternal liver trio.

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“…Very little is known about these protective mechanisms in human fetal tissues. The epoxide hydrolase activity, which is involved in the detoxification of biologically active epoxides is found at a much lower level in fetal than in adult liver (17).…”

Section: Carcinogen Metabolism and Dna Repairmentioning

confidence: 99%

Transplacental transfer of genotoxins and transplacental carcinogenesis.

Autrup

1993

Environ Health Perspect

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A number of chemical compounds induce cancer in the offspring of animals treated with these compounds. The fetus is sensitive to the toxic and teratogenic effects of chemicals in the early embryonic stages, whereas it is sensitive to carcinogenic effects during late fetal stages. Carcinogens may be direct acting or may require metabolic oxidation such as those in tobacco smoke. Activation can occur in utero. Animal experiments indicate that tumors can be initiated in utero, commonly by activation of cellular proto-oncogenes, and that promotion can occur after birth by postnatal treatment with tumor promoters. This may have important implications for humans. The initial peak of cancer incidence during the first 5 years of life may be due to prenatal exposure of either parent to mutagens, but the role of paternal exposure in relation to childhood cancer is controversial. There is an increased risk of cancer in children whose fathers work in heavy industry or whose mothers work in medical or dental services. The exact etiological agents have not been unequivocally identified. Information on human transplacental exposure to carcinogens and genotoxins is limited and based on measurement of maternal plasma concentrations or analysis of cord blood. Transplacental transfer of carcinogens in smoke and smoke-related damage to fetal tissue have been demonstrated. The mycotoxin aflatoxin B1 or its metabolites have been detected in cord blood, as have metabolites of pesticides and polychlorinated biphenyls. New biomarkers may provide important information on the transplacental transfer of genotoxic compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

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Cytosolic epoxide hydrolase in fetal and adult human liver

Cited by 26 publications

References 33 publications

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

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

Molecular bases of the fetal liver–placenta–maternal liver excretory pathway for cholephilic compounds

Transplacental transfer of genotoxins and transplacental carcinogenesis.

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