Expression and inducibility of P450 enzymes during liver ontogeny

Rich, Kim J.; Boobis, Alan R.

doi:10.1002/(sici)1097-0029(19971201)39:5<424::aid-jemt5>3.0.co;2-g

Cited by 81 publications

(39 citation statements)

References 62 publications

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“…However, much is not known about how and when the xenobiotic-metabolizing P450 genes become activated or suppressed after hematopoiesis but before adulthood. Understanding the regulation of ontogenic expression is important because ontogeny affects both the expression and inducibility of xenobioticmetabolizing genes during postnatal liver development (Fouts and Adamson, 1959;Rich and Boobis, 1997).…”

mentioning

confidence: 99%

Three Patterns of Cytochrome P450 Gene Expression during Liver Maturation in Mice

Hart¹,

Cui²,

Klaassen³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The neonatal period of liver development is an often overlooked phase of development. For instance, ontogeny of xenobioticmetabolizing enzymes can markedly affect biotransformation as the liver matures. To systematically examine the ontogenic gene expression patterns of cytochrome P450 genes (P450) in mice, the gene expression profiles of 19 xenobiotic-metabolizing P450 in Cyp1 to 4 families were determined. The mRNA levels in C57BL/6 mouse livers were quantified using branched DNA technology at the following ages: gestational day 17 (2 days before birth) and postnatal days 0, 1, 3, 5, 10, 15, 20, 30, and 45. Among the 13 P450 genes expressed in mouse livers, three distinct ontogenic expression patterns were identified by cluster analysis. Genes in group 1 (Cyp3a16 as well as 3a41b in male) were expressed in the perinatal period, but they were essentially nondetectable by 30 days of age. Genes in group 2 (Cyp2e1, 3a11, and 4a10 as well as 3a41b in female) quickly increased after birth and reached maximal expression levels by day 5. Genes in group 3 (Cyp1a2, 2a4, 2b10, 2c29, 2d22, 2f2, 3a13, and 3a25) were expressed at low levels until days 10 to 15, but they markedly increased at day 20 to a high and stable level. In conclusion, the developmental expression of P450 in mouse liver can be divided into three patterns, suggesting that different mechanisms are responsible for the expression of P450 during liver maturation.

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mentioning

confidence: 99%

Three Patterns of Cytochrome P450 Gene Expression during Liver Maturation in Mice

Hart¹,

Cui²,

Klaassen³

et al. 2008

Drug Metab Dispos

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“…Roscovitine is metabolized mainly by the CYP3A4 and CYP2B6 enzymes in human [139]. Several CYP450 enzymes are not fully matured in rats at two weeks of age [150]. A similar situation was also reported in humans; CYP3A4, for example, only approaches full maturity after the first year of life [151,152].…”

Section: Age-dependent Kinetics and Pharmacodynamics Of Roscovitine Imentioning

confidence: 57%

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

Zhelev

Trifonov²,

Wang³

et al. 2013

Biodiscovery

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This monograph reviews the discovery and development of the cyclindependent kinase inhibitor roscovitine (R-roscovitine, CYC202, Seliciclib). The authors summarise the in vitro and in vivo data that have formed the basis for clinical investigation of Seliciclib as an anti-cancer drug. Kinase selectivity, cellular effects and the pharmacological properties of the drug are discussed in addition to the clinical results of Seliciclib being reviewed. Novel results on the effect of the drug in cardiac hypertrophy are summarized and potential applications of Seliciclib in other therapeutic areas, including, inflammation, virology, glomerulonephritis and polycystic kidney disease, are discussed. Finally the authors argue that optimisation of the therapeutic effect of kinase inhibitors such as Seliciclib can be enhanced using a systems biology approach involving mathematical modelling of the molecular pathways regulating cell growth and division. Seliciclib -discovery and developmentBioDiscovery 2 December 2013 | Issue 10 | 1

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“…As with human neonates, the metabolic ability of the newborn rat is known to be extremely immature, with a low cytochrome P450 content (Rich and Boobis, 1997) and a low capacity for glucuronidation (Gow et al, 2001). Therefore, it could be predicted that chemicals directly exerting adverse effects might show stronger toxicity in the newborn than in young/adult rats.…”

Section: Discussionmentioning

confidence: 99%

“…The rate of production of active metabolites, including free radical intermediates, would be expected to be significantly less or negligible in newborn animals at least around 50 mg/kg, at which clearly hepatic changes were observed in young rats for both chemicals, because of their lower content of cytochrome P450 (Rich and Boobis, 1997). This metabolic character for both chemicals as well as the lower blood flow to the liver during the newborn period (Gow et al, 2001) would make a major contribution to the much higher NOAEL in the newborn than in young rats.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility of Newborn Rats to Hepatotoxicity of 1,3-Dibromopropane and 1,1,2,2-Tetrabromoethane, Compared With Young Rats

et al. 2005

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-Newborn rat studies were conducted with oral administration of 1,3-dibromopropane (DBP) and 1,1,2,2-tetrabromoethane (TBE) from postnatal Days 4 to 21 to allow comparison of NOAELs and unequivocally toxic levels with those from 28-day young rat studies starting at 5-6 weeks of age. The unequivocally toxic level was estimated by our specified criteria, requiring simultaneous change of organ weights, histopathology, some biochemical parameters and body weights, because in this study only hypertrophy of hepatocytes was observed as a major histopathological change. DBP caused centrilobular hypertrophy of hepatocytes with alteration in biochemical parameters, as well as lowering of body weights, regardless of sex, in both newborn and young rats. NOAELs and unequivocally toxic levels were considered to be 50 and 150 mg/kg/day in newborn rats and 10 and 250 mg/kg/day in young rats, respectively. In the newborn rat study of TBE, some hepatic effects observed at the top dose of 50 mg/kg were not considered adverse because of the lack of histopathological changes. Significant lowering of body weight was noted at 200 mg/kg in the dose-finding study but histopathological data were not available. In the young rat study, there was no definite toxicity at 6 mg/kg and hypertrophic changes in liver and thyroids without body weight change occurred at 200 mg/kg. There were no clear sex differences in both the newborn and young rat studies. NOAELs were considered to be 50 and 6 mg/kg/day in newborn and young rats, respectively, but unequivocally toxic levels for both rats could not be estimated. Abnormalities of external and sexual development and reflex ontogeny in the newborn were not observed with either chemical. Based on these results, it can be concluded that the target organ of DBP and TBE is the liver in both newborn and young rats, and that while the doses at which toxic signs began to appear are higher in newborn rats, those causing clear toxicity may be paradoxically lower in the newborn case.

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Expression and inducibility of P450 enzymes during liver ontogeny

Cited by 81 publications

References 62 publications

Three Patterns of Cytochrome P450 Gene Expression during Liver Maturation in Mice

Three Patterns of Cytochrome P450 Gene Expression during Liver Maturation in Mice

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

Susceptibility of Newborn Rats to Hepatotoxicity of 1,3-Dibromopropane and 1,1,2,2-Tetrabromoethane, Compared With Young Rats

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