Expression of xenobiotic-metabolizing cytochrome P450 forms in human adult and fetal liver

Hakkola, Jukka; Pasanen, Markku; Purkunen, Raija; Saarikoski, Seppo; Pelkonen, Olavi; Mäenpää, J; Rane, Anders; Raunio, Hannu

doi:10.1016/0006-2952(94)90223-2

Cited by 179 publications

(98 citation statements)

References 36 publications

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“…11) CYP1A2, CYP2F1, and CYP4B1 were absent in the fetal liver, which is in agreement with the literature. 20,21) In addition, the mRNA expression proles in these cases showed no overlap among molecular species. Although the specicity for the ex pression of the mRNAs of CYP11B1 and 11B2 was veried only for the adrenal gland, the sequences of the primers and the probe were specied based on a homology study by performing an NCBI BLAST search.…”

Section: Resultsmentioning

confidence: 74%

Tissue Distribution of mRNA Expression of Human Cytochrome P450 Isoforms Assessedby High-Sensitivity Real-Time Reverse Transcription PCR

et al. 2003

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Pairs of forward and reverse primers and TaqMan probes specic to each human cytochrome P450 isoform were prepared. Analysis of the mRNA level of each CYP isoform in total RNA from pooled specimens of various human or gans was performed by realtime reverse transcription PCR using an ABI PRISM 7700 sequence detector system. The ex pression of CYP3A4 mRNA was similar to that of CYP3A7 mRNA in the fetal liver, and CYP3A4 mRNA levels in the fetal liver were about 0.1 times lower than in the adult liver. CYP2E1 showed the highest level of mRNA expression in the liver. The mRNA expression of 30 CYP isoforms (CYP1A1, 1A2, 1B1, 2A6, 2A7, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2J2, 3A4, 3A5, 3A7, 4A11, 4F2, 4F3, 5A1, 7B1, 8A1, 8B1, 17, 26A1, 27, 27B1, 39A1, 46, and 51) in the liver was successfully detected by this method. CYP2F1, 4B1, 4F8, 11s (11A, 11B1, and 11B2), 19, and 24 mRNA levels were the highest in the lung, lung, prostate, adrenal gland, placenta, and kidney, respectively; however, the mRNA expression of these eight CYP isoforms in the liver was not detected by this method. The mRNA levels of the CYP isoforms deter mined in various human tissues were in good agreement with previously reported data. The method described here has the advantages of high specicity and excellent quantication over a wide range of mRNA concentrations, making it suitable for the evaluation of a large number of samples in the assessment of the expression prole of drugmetabolizing enzymes.

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Section: Resultsmentioning

confidence: 74%

Tissue Distribution of mRNA Expression of Human Cytochrome P450 Isoforms Assessedby High-Sensitivity Real-Time Reverse Transcription PCR

et al. 2003

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“…2), as shown before in the adult liver. 36 We concluded that CYP3A4 and CYP3A5 are the predominant forms of CYP3A expression in the biliary epithelium. Furthermore, the steroid 6␤-hydroxylase activity in gallbladder-derived BEC as compared with hepatocytes was consistent with the fact that CYP3A protein content in BEC was not only less FIG.…”

Section: Discussionmentioning

confidence: 78%

Phase I and Phase II drug-metabolizing enzymes are expressed and heterogeneously distributed in the biliary epithelium

et al. 1999

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Tissue expression of drug-metabolizing enzymes influences susceptibility to drugs and carcinogens. Because the biliary epithelium, exposed to bile-borne chemicals, may give rise to drug-induced cholangiopathies and to cholangiocarcinomas, we determined the pattern of expression of drug-metabolizing enzymes in this epithelium. We first demonstrated by blot analyses that biliary epithelial cells (BEC) isolated from human gallbladders display cytochrome P450 (CYP) 1A, 2E1, and 3A, microsomal epoxide hydrolase (mEH), ␣, , and glutathione S-transferase (GST), transcripts and proteins. We also identified CYPassociated steroid 6␤-hydroxylase activity in BEC. CYP and mEH expression was 5-to 20-fold lower in BEC than in autologous hepatocytes, and further differed by a higher ratio of CYP3A5/CYP3A4, and by CYP1A1 predominance over CYP1A2. ␣GST was highly expressed in both hepatocytes and BEC, while GST was restricted to BEC. In approximately 50% of individuals, GST was expressed in hepatocytes and at lower levels in BEC. By using the same antibodies as those used in immunoblots, we could show by immunohistochemistry that CYP2E1, CYP3A, mEH, ␣, , and GST immunoreactivities are expressed and display a heterogeneous distribution in the epithelium lining the entire biliary tract except for small intrahepatic bile ducts that were devoid of CYP3A and ␣GST immunoreactivities. In conclusion, BEC contribute to phase II, and although to a lesser extent than hepatocytes, to phase I biotransformation. The distribution of drug-metabolizing enzymes in BEC suggest that they are heterogeneous in their ability to generate and detoxicate reactive metabolites, which may contribute to specific distributions of cholangiopathies. (HEPATOLOGY 1999;30:1498-1506.)Foreign compounds including procarcinogens and drugs are widely distributed in our environment. The liver is the major organ responsible for their biotransformation into more hydrophilic products, and elimination through bile secretion. Biotransformation results from the activities of phase I and phase II metabolizing enzymes that are mainly, although not exclusively, located within hepatocytes.

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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%

“…Expression of CYP2C protein and activity in foetal liver appears to be negligible (Ratanasavanh et al 1991;Hakkola et al 1994;Treluyer et al 1996Treluyer et al & 1997. CYP2C mRNA and protein expression are significantly elevated as early as the first postnatal day (Ratanasavanh et al 1991, Treluyer et al 1996& 1997, protein expression increases during the first week and CYP2C activity (tolbutamide hydroxylation) surges after the first week and remains at about 40% of the adult level during the first year (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

102

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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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Expression of xenobiotic-metabolizing cytochrome P450 forms in human adult and fetal liver

Cited by 179 publications

References 36 publications

Tissue Distribution of mRNA Expression of Human Cytochrome P450 Isoforms Assessedby High-Sensitivity Real-Time Reverse Transcription PCR

Tissue Distribution of mRNA Expression of Human Cytochrome P450 Isoforms Assessedby High-Sensitivity Real-Time Reverse Transcription PCR

Phase I and Phase II drug-metabolizing enzymes are expressed and heterogeneously distributed in the biliary epithelium

Neonatal Hepatic Drug Elimination

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