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

Cazeneuve, Cécile; Pons, Gérard; Rey, Elisabeth; Tréluyer, J.M.; Cresteil, T.; Thiroux, G; d’Athis, Philippe; Olivé, G

doi:10.1111/j.1365-2125.1994.tb05706.x

Cited by 94 publications

(35 citation statements)

References 18 publications

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“…P450 1-3 family enzymes play major roles in drug metabolism, whereas P450 family 4 enzymes primarily metabolize endogenous compounds such as eicosanoids. Prior reports on the P450 1A subfamily have been contentious, with argument for little to no expression, or for highly variable expression across prenatal development (Omiecinski et al, 1990;Murray et al, 1992;Cazeneuve et al, 1994;Hakkola et al, 1994Hakkola et al, , 1997Shimada et al, 1996;Sonnier and Cresteil, 1998;Choudhary et al, 2005;Bieche et al, 2007). By qRT-PCR, we determined that gene expression levels are negligible to very low, but some extreme outliers were identified (e.g., CYP1A2 in liver 633; Fig.…”

Section: Resultsmentioning

confidence: 99%

Hepatic Cytochrome P450 Activity, Abundance, and Expression Throughout Human Development

Sadler

Nandhikonda

Webb-Robertson

et al. 2016

Drug Metabolism and Disposition

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Cytochrome P450s are oxidative metabolic enzymes that play critical roles in the biotransformation of endogenous compounds and xenobiotics. The expression and activity of P450 enzymes varies considerably throughout human development; the deficit in our understanding of these dynamics limits our ability to predict environmental and pharmaceutical exposure effects. In an effort to develop a more comprehensive understanding of the ontogeny of P450 enzymes, we employed a multi-omic characterization of P450 transcript expression, protein abundance, and functional activity. Modified mechanism-based inhibitors of P450s were used as chemical probes for isolating active P450 proteoforms in human hepatic microsomes with developmental stages ranging from early gestation to late adult. High-resolution liquid chromatography-mass spectrometry was used to identify and quantify probe-labeled P450s, allowing for a functional profile of P450 ontogeny. Total protein abundance profiles and P450 rRNA was also measured, and our results reveal life-stage-dependent variability in P450 expression, abundance, and activity throughout human development and frequent discordant relationships between expression and activity. We have significantly expanded the knowledge of P450 ontogeny, particularly at the level of individual P450 activity. We anticipate that these results will be useful for enabling predictive therapeutic dosing, and for avoiding potentially adverse and harmful reactions during maturation from both therapeutic drugs and environmental xenobiotics.

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Section: Resultsmentioning

confidence: 99%

Hepatic Cytochrome P450 Activity, Abundance, and Expression Throughout Human Development

Sadler

Nandhikonda

Webb-Robertson

et al. 2016

Drug Metabolism and Disposition

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“…The maturation of CYP1A2 was delayed compared to other cytochrome P450 isoforms (Cresteil 1998;Sonnier & Cresteil 1998). Using caffeine N-3-demethylation in vitro as a marker for CYP1A2 (Butler et al 1989), Cazeneuve et al (1994) similarly showed a rise in CYP1A2 activity during this period, reaching a plateau at around 120 days.…”

Section: Cytochrome P450 In the Neonatal Human Livermentioning

confidence: 95%

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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“…Caffeine metabolism was studied in human liver microsomes from foetuses, neonates, infants and adults (Cazeneuve et al, 1994). The formation of dimethylxanthines (paraxanthine, theophylline and theobromine) was significantly less in foetuses, neonates and infants than in adults, as observed previously in vivo, whereas the formation of 1,3,7-trimethyluric acid (C-8 hydroxylation) was not significantly different between the age groups.…”

Section: Methylxanthine Exposure Of the Foetusmentioning

confidence: 66%

“…In premature infants, caffeine is only metabolised to theophylline and is to a large extent excreted unchanged in the urine (Berthou et al, 1988). When CYP1A2 develops after the third to fifth month of life (Sonnier and Cresteil, 1998), N-3 and N-7 demethylations begin, and the infant demonstrates the metabolic pattern that characterises mature hepatic metabolism (Berthou et al, 1988;Kraus et al, 1993;Cazeneuve et al, 1994). Hydroxylation capability matures as early as one month in some children, and may be higher in infants than in adults.…”

Section: Methylxanthine Exposure Of the Newbornmentioning

confidence: 99%

“…Although CYP1A2 is not present in any quantity during foetal life , foetal tissue can demethylate caffeine in vitro (Cazenauve et al, 1994). CYP3A7 may be the cytochome enzyme responsible, as both the level of CYP3A7 and the demethylation capacity decline in late pregnancy (Cazeneuve et al, 1994;Kitada et al, 1987). Clinical documentation for CYP1A2's gradual emergence in the early months of postnatal life is widely available because theophylline and caffeine are extensively used for the treatment of apnea in premature deliveries, newborns, and infants.…”

Section: Methylxanthine Exposure Of the Newbornmentioning

confidence: 99%

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Intake of caffeine and other methylxanthines during pregnancy and risk for adverse effects in pregnant women and their foetuses

Andersson¹,

Hallström²,

Kihlman³

2005

TemaNord

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

Cited by 94 publications

References 18 publications

Hepatic Cytochrome P450 Activity, Abundance, and Expression Throughout Human Development

Hepatic Cytochrome P450 Activity, Abundance, and Expression Throughout Human Development

Neonatal Hepatic Drug Elimination

Intake of caffeine and other methylxanthines during pregnancy and risk for adverse effects in pregnant women and their foetuses

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