Hormonal Regulation of Hepatic Drug-Metabolizing Enzyme Activity During Adolescence

Kennedy, Mary Jayne

doi:10.1038/clpt.2008.202

Cited by 69 publications

(55 citation statements)

References 72 publications

(73 reference statements)

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“…However, developmental profiles of DME expression and activity closely reflect that of major shifts in hormonal levels associated with growth and sexual maturation (Leeder and Kearns, 1997). Growth and/or sex hormones can potentially serve as biochemical regulators of DME expression through interaction with nuclear hormone receptors such as the pregnane X receptor and/or the constitutive androstane receptor (Kennedy, 2008). Hosokawa and Satoh (1988) reported that the expression of carboxylesterase isoenzymes RL1 and RH1 in the liver of hypophysectomized rats was significantly decreased after the treatment of HGH.…”

Section: Discussionmentioning

confidence: 99%

Age- and Sex-Related Expression and Activity of Carboxylesterase 1 and 2 in Mouse and Human Liver

Zhu¹,

Appel²,

Jiang³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Carboxylesterase (CES) 1 and CES2 are two major hepatic hydrolases responsible for the metabolism of numerous endogenous and exogenous compounds. In this study, age-and sex-dependent expression and activity of CES1 and CES2 were investigated using both animal models and individual human liver s9 samples. The expression and activity of mouse CES1 (mCES1) and mCES2 in the liver were markedly lower in newborns relative to adults and increased gradually with age, approximating levels of adult animals by age 2 to 4 weeks. Likewise, the average human CES1 (hCES1) expression in the subjects <1 year of age was significantly lower than that of pooled samples. In particular, hCES1 expression in the 13-day and 1-month-old subjects was just 20.3 and 11.1%, respectively, of the pooled sample values. In addition, the subjects <1 year of age exhibited a trend suggestive of low hCES2 expression, but this difference failed to reach statistical significance because of large interindividual variability. The expression and activity of mCES1 and mCES2 were not significantly altered after the animals were treated with human growth hormone, indicating growth hormone may not be associated with the low level of CES expression during early developmental stages. No significant differences of the expression and activity of mCES1 and mCES2 were observed between sexually mature male and female mice. In conclusion, the expression and activity of CES1 and CES2 are age-related but independent of growth hormone level. Sex seems to be an unlikely factor contributing to the regulation of CES1 and CES2.Carboxylesterase (CES) 1 and CES2 are two major hydrolytic enzymes responsible for the metabolism of numerous carboxylic acid esters, carbamates, thioesters, and amide agents. A variety of widely prescribed therapeutic drugs such as methylphenidate (MPH), oseltamivir, and irinotecan are metabolized by CES1 and/or CES2, resulting in the formation of hydrolytic metabolites (Imai et al., 2006;Hosokawa et al., 2008).

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Section: Discussionmentioning

confidence: 99%

Age- and Sex-Related Expression and Activity of Carboxylesterase 1 and 2 in Mouse and Human Liver

Zhu¹,

Appel²,

Jiang³

et al. 2009

Drug Metab Dispos

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“…The expression of CYP2C19 and FMO is somewhat higher in children versus adults; however, it is not clear whether this difference in expression is sufficient to explain greater metabolic clearance of voriconazole in children versus adults. It is interesting to note that other drugs that are predominantly metabolized by hepatic CYP2C9/19 such as phenytoin, omeprazole, and sirolimus show higher clearance in children between 2 and 10 years of age than in adults (Litalien et al, 2005;Filler et al, 2008;Kennedy, 2008). It would be interesting to identify drugs that are predominantly metabolized by FMO3 and examine their clearance in children versus adults.…”

Section: Discussionmentioning

confidence: 99%

“…These factors include organ maturation, body composition, changes in liver size, liver blood flow, extent of plasma protein binding, changes in the hormonal levels, and alteration in the expression and/or catalytic activity of some of the drug-metabolizing enzymes (Hines and McCarver, 2002;Kearns et al, 2003;Chen et al, 2006;Kennedy, 2008). For example, drugs that are metabolized by hepatic CYP2C9/19, such as phenytoin, omeprazole, and sirolimus, show higher clearance in children between 2 and 10 years of age than in adults (Litalien et al, 2005;Kennedy 2008;Filler et al, 2008).…”

mentioning

confidence: 99%

In Vitro Hepatic Metabolism Explains Higher Clearance of Voriconazole in Children versus Adults: Role of CYP2C19 and Flavin-Containing Monooxygenase 3

Yanni¹,

Annaert²,

Augustijns³

et al. 2009

Drug Metab Dispos

117

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ABSTRACT:Voriconazole is a broad spectrum antifungal agent for treating life-threatening fungal infections. Its clearance is approximately 3-fold higher in children compared with adults. Voriconazole is cleared predominantly via hepatic metabolism in adults, mainly by CYP3A4, CYP2C19, and flavin-containing monooxygenase 3 (FMO3). In vitro metabolism of voriconazole by liver microsomes prepared from pediatric and adult tissues (n ‫؍‬ 6/group) mirrored the in vivo clearance differences in children versus adults, and it showed that the oxidative metabolism was significantly faster in children compared with adults as indicated by the in vitro half-life (T 1/2 ) of 33.8 ؎ 15.3 versus 72.6 ؎ 23.7 min, respectively. The K m for voriconazole metabolism to N-oxide, the major metabolite formed in humans, by liver microsomes from children and adults was similar (11 ؎ 5.2 versus 9.3 ؎ 3.6 M, respectively). In contrast, apparent V max was approximately 3-fold higher in children compared with adults (120.5 ؎ 99.9 versus 40 ؎ 13.9 pmol/min/mg). The calculated in vivo clearance from in vitro data was found to be approximately 80% of the observed plasma clearance values in both populations. Metabolism studies in which CYP3A4, CYP2C19, or FMO was selectively inhibited provided evidence that contribution of CYP2C19 and FMO toward voriconazole N-oxidation was much greater in children than in adults, whereas CYP3A4 played a larger role in adults. Although expression of CYP2C19 and FMO3 is not significantly different in children versus adults, these enzymes seem to contribute to higher metabolic clearance of voriconazole in children versus adults.

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“…5, 2010 HEPATIC ENZYME INDUCTION AND CLINICAL PATHOLOGY DME induction, partly because of a greater liver-to-body weight ratio and differences with adults in metabolic and protein binding capacity, and renal and hepatic function (Ginsberg et al 2004;Kennedy 2008;Moreland et al 1982). Hormonal changes with puberty are thought to further influence CYP3A4 regulation (Kennedy, 2008). In an exemplary study of children receiving long-term PB and/or PHE (Aiges et al 1980), increased activity of one or more routinely measured serum hepatobiliary marker enzymes was reported in all subjects.…”

Section: Hepatobiliary Biomarker Findings In Association With Prototymentioning

confidence: 99%

Effects of Hepatic Drug-metabolizing Enzyme Induction on Clinical Pathology Parameters in Animals and Man

et al. 2010

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Hepatic drug-metabolizing enzyme (DME) induction is an adaptive response associated with changes in preclinical species; this response can include increases in liver weight, hepatocellular hyperplasia and hypertrophy, and upregulated tissue expression of DMEs. Effects of DME induction on clinical pathology markers of hepatobiliary injury and function in animals as well as humans are not well established. This component of a multipart review of the comparative pathology of xenobiotically mediated induction of hepatic metabolizing enzymes reviews pertinent data from retrospective and prospective preclinical and clinical studies. Particular attention is given to studies with confirmation of DME induction and concurrent evaluation of liver and/or serum hepatobiliary marker enzyme activities and histopathology. These results collectively indicate that in the rat, when histologic findings are limited to hepatocellular hypertrophy, DME induction is not expected to be associated with consistent or substantive changes in serum or plasma activity of hepatobiliary marker enzymes such as alanine aminotransferase, alkaline phosphatase, and gamma glutamyltransferase. In the dog and the monkey, published studies also do not demonstrate a consistent relationship across DME-inducing agents and changes in these clinical pathology parameters. However, increased liver alkaline phosphatase or gamma glutamyltransferase activity in dogs treated with phenobarbital or corticosteroids suggests that direct or indirect induction of select hepatobiliary injury markers can occur both in the absence of liver injury and independently of induction of DME activity. Although correlations between tissue and serum levels of these hepatobiliary markers are limited and inconsistent, increases in serum/plasma activities that are substantial or involve changes in other markers generally reflect hepatobiliary insult rather than DME induction. Extrahepatic effects, including disruption of the hypothalamic-pituitary-thyroid axis, can also occur as a direct outcome of hepatic DME induction in humans and animals. Importantly, hepatic DME induction and associated changes in preclinical species are not necessarily predictive of the occurrence, magnitude, or enzyme induction profile in humans.

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Hormonal Regulation of Hepatic Drug-Metabolizing Enzyme Activity During Adolescence

Cited by 69 publications

References 72 publications

Age- and Sex-Related Expression and Activity of Carboxylesterase 1 and 2 in Mouse and Human Liver

Age- and Sex-Related Expression and Activity of Carboxylesterase 1 and 2 in Mouse and Human Liver

In Vitro Hepatic Metabolism Explains Higher Clearance of Voriconazole in Children versus Adults: Role of CYP2C19 and Flavin-Containing Monooxygenase 3

Effects of Hepatic Drug-metabolizing Enzyme Induction on Clinical Pathology Parameters in Animals and Man

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