The presence of a monooxygenase system in human fetal liver microsomes

Yaffe, Sumner J.; Rane, Anders; Sjöqvist, Folke; Boréus, L. O.; Orrenius, Sten

doi:10.1016/0024-3205(70)90038-x

Cited by 151 publications

(46 citation statements)

References 18 publications

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“…To our knowledge, this is the first report of repeated supratherapeutic ingestions of APAP during pregnancy resulting in liver transplantation. While the risk to the mother from APAP poisoning is paramount, there is concern that because APAP crosses the placenta and fetal livers demonstrate mixed-function oxidase activity by 14 weeks gestational age, fetal liver damage may occur [5,9]. We were unable to document this in our case.…”

Section: Discussionmentioning

confidence: 74%

Unintentional Chronic Acetaminophen Poisoning During Pregnancy Resulting in Liver Transplantation

Thornton

Minns

2012

J. Med. Toxicol.

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Introduction Acetaminophen (APAP) is a widely used medication in pregnancy and is considered safe. Unfortunately, APAP is also among the most commonly reported agents implicated in overdoses during pregnancy. We present a unique case of a pregnant patient with fulminant hepatic failure resulting in a liver transplant from repeated supratherapeutic ingestions of APAP. Case Report A 22 year pregnant female presented with abdominal pain and hepatotoxicity after taking supratherapeutic amounts of APAP to treat dental pain. The patient denied intentional or acute ingestion of APAP but did admit to taking approximately 8-9 grams of APAP per day for 10-14 days for dental pain. Other cause of hepatotoxicity, including acute fatty liver of pregnancy, were evaluated for and ruled out. She developed fulminant hepatic failure and required liver transplantation which was successful. The pregnancy remained viable through the operation but intrauterine fetal demise occurred 2 weeks later. An MRI of the fetus showed extensive peri-cerebral and intraventricular hemorrhage with extensive periventricular leukomalacia. Discussion The degree of morbidity from repeated supratherapeutic ingestions of APAP seen in this case is rare and poorly described in a pregnant patient. There are no prior reports describing the need for liver transplant after repeated supratherapeutic ingestions of APAP during pregnancy. Along with the typical cause of hepatotoxicy several unique pregnancy-related causes also had to be evaluated for. This case highlights the significant morbidity that can occur with even unintentional APAP toxicity and the need to educate patients, especially pregnant patients, of the risk of excessive APAP use.

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Section: Discussionmentioning

confidence: 74%

Unintentional Chronic Acetaminophen Poisoning During Pregnancy Resulting in Liver Transplantation

Thornton

Minns

2012

J. Med. Toxicol.

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“…27,[40][41][42] However, little is known concerning the induction of drug-metabolizing enzymes in HFL, because research with pregnant or fetus should be never attempted due to ethical considerations. The induction of CYP in HepG2 cells has been studied as a model of human liver.…”

Section: Expression Of Pxr and Gra A In Hepg2 And Hfl Cells Rt-pcr Wamentioning

confidence: 99%

Comparison of Basal Gene Expression and Induction of CYP3As in HepG2 and Human Fetal Liver Cells

Maruyama

Matsunaga

Harada

et al. 2007

Biological & Pharmaceutical Bulletin

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Cytochrome P450 (CYP) is a gene superfamily of hemoproteins that catalyze the oxidation of lipophilic substrates to more water-soluble products. Among them, the human CYP3A subfamily contains mainly three isoforms, CYP3A4, CYP3A5, and CYP3A7. 1) CYP3A4 is the predominant isoform expressed in adult human liver and intestine, 2,3) and plays a significant role in the metabolism of endogenous and exogenous compounds. 4) CYP3A5 is expressed polymorphically throughout development in the liver.5,6) CYP3A7 is a major CYP isoform in the human fetal and newborn liver. 7)The levels of expression of CYP3A isoforms are enhanced by treatment with various agents, such as rifampicin (RIF), phenobarbital, clotrimazole, and dexamethasone (DEX). [8][9][10] Unlike the fetal liver in most experimental animals, the human fetus supports the oxidative metabolism of a wide range of drugs and other xenobiotics. 11) Toxicological and pharmacological studies designed to assess the safety and efficacy of candidate drugs and chemicals in the human fetus depend greatly on extrapolation from animal models. However, it has been difficult to estimate alterations of drug metabolism by inducers of drug-metabolizing enzymes in the human fetus due to the problem of differences among species.12) Species differences in the inducibility of drug-metabolizing enzymes 13,14) result in important differences in the metabolism of drugs and potential carcinogens. The induction of CYP3A in human-derived cell lines has been studied as a model of human tissues.15) As research with human subjects, especially when pregnant, should be restricted due to ethical considerations, human fetal in vitro models have been evaluated with increasing frequency to find those that are most suitable for predicting human responses in vivo.The HepG2 cell line was established from a liver tumor biopsy specimen from a 15-year-old Caucasian male subject.16) This cell line has features of hepatoblast-like cells, because the cells express CYP3A7 17) and secrete a-fetoprotein (AFP) 16) into the cell culture medium, both proteins that are found predominantly in human fetal hepatocytes.7) However, it is unknown whether HepG2 is a useful cell line as a human fetal liver (HFL) model for experiments regarding drug metabolism, because there have been no comparisons of gene expression between HFL and HepG2 cells, and limited data are available regarding comparison of the responses of HepG2 and HFL cells to inducers.In the present study, to characterize the expression and induction of CYP in HFL cells, the basal gene expression patterns and inducibility of CYP, especially CYP3A isoforms, were compared to those in HepG2 cells. MATERIALS AND METHODS ChemicalsDulbecco's phosphate-buffered saline (PBS) was from Dainippon Pharmaceutical Co. (Osaka, Japan). Dulbecco's modified Eagle's medium and Williams' medium E were purchased from Sigma Chemical Co. (St. Louis, MO, U.S.A.). Penicillin-streptomycin-neomycin antibiotic mixture and SuperScript First-Strand Synthesis System for reverse transcription-po...

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“…The first observations of oxidative drug metabolism in human foetal liver were made by Yaffe et al (1970) and Pelkonen et al (1971), and although incomplete, a significant amount of data has been obtained over more recent years about foetal and neonatal hepatic P450 isoforms (Treluyer et al 1991(Treluyer et al & 1996Kitada & Kamataki 1994;Hakkola et al 1994;Vieira et al 1996;Hakkola et al 1998). At birth, total neonatal hepatic cytochrome P450 concentration is approximately 30% of adult levels (Treluyer et al 1996(Treluyer et al & 1997.…”

Section: Cytochrome P450 In the Neonatal Human Livermentioning

confidence: 99%

Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

104

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After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood flow and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life. These changes which may well affect the capacity of neonatal hepatic drug metabolism. The hepatic expression of cytochromes P450 1A2, 2C, 2D6, 2E1 and 3A4 develop at different rates in the postnatal period, whilst 3A7 expression diminishes. Hepatic glucuronidation in the human neonate is relatively immature at birth, which contrasts with the considerably more mature neonatal hepatic sulfation activity. Limited in vivo studies show that the human neonate can significantly metabolise xenobiotics but clearance is considerably less compared with the older infant and adult. The neonatal population included in pharmacological studies is highly heterogeneous with respect to age, body weight, ductus venosus closure and disease processes, making it difficult to interpret data arising from human neonatal studies. Studies in the perfused foetal and neonatal sheep liver have demonstrated how the oxidative and conjugative hepatic elimination of drugs by the intact organ is significantly increased during the first week of life, highlighting that future studies will need to consider the profound physiological changes that may influence neonatal hepatic drug elimination shortly after birth.The development of clinical pharmacology has resulted in a more rational approach to drug therapy, as well as a deeper understanding of the factors capable of influencing drug disposition, and hence drug effects. Of these factors, age is of great importance. However, substantial differences in drug disposition not only exist between neonates and adults, but also among premature neonates, term neonates, infants and children.During the last two decades drug disposition in the neonatal period has been studied extensively. A major impetus for these studies seems to have been a series of incidents involving illness or death following the administration of drugs at ratios of dose/body weight innocuous in an adult (Craft et al. 1974;Gershanik et al. 1982). These studies have shown that the transition from neonate to childhood is characterised by the ontogeny of all of the processes of drug absorption, distribution, hepatic metabolism and renal excretion, with the development of hepatic drug metabolism being particularly important.The extent to which the neonatal drug-metabolising en-

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The presence of a monooxygenase system in human fetal liver microsomes

Cited by 151 publications

References 18 publications

Unintentional Chronic Acetaminophen Poisoning During Pregnancy Resulting in Liver Transplantation

Unintentional Chronic Acetaminophen Poisoning During Pregnancy Resulting in Liver Transplantation

Comparison of Basal Gene Expression and Induction of CYP3As in HepG2 and Human Fetal Liver Cells

Neonatal Hepatic Drug Elimination

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