Age-related changes in the mRNA levels of CYP1A1, CYP2B1/2 and CYP3A1 isoforms in rat small intestine

Pałasz, Artur; Wiaderkiewicz, Anna; Wiaderkiewicz, Ryszard; Czekaj, Piotr; Czajkowska, Beata I.; Lebda-Wyborny, Tomasz; Piwowarczyk, Aneta; Bryzek, Aleksandra

doi:10.1007/s12263-011-0240-z

Cited by 10 publications

(10 citation statements)

References 44 publications

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“…6). The high intestinal ability for detoxification in aged rats is also supported by the age-independent expression of P450s and age-dependent increase of UGT activity in rat intestine (Warrington et al, 2004;Bolling et al, 2011;Pałasz et al, 2012).…”

Section: Age-related Rat Hepatic and Intestinal Ces Expression 271mentioning

confidence: 83%

“…It has been reported that the expression of several metabolizing enzymes, e.g., P450 and UDPglucuronosyltransferase (UGT), is altered with aging in both rat liver and intestine. The rat hepatic expression of P450 decreases with aging (Warrington et al, 2003(Warrington et al, , 2004Yun et al, 2010), while ageindependent P450 expression has been shown in rat intestine (Warrington et al, 2004;Pałasz et al, 2012). With respect to UGT activity, no change or an age-dependent increase has been observed in rat liver and intestine, respectively (Lee et al, 2008;Bolling et al, 2011).…”

Section: Tablementioning

confidence: 98%

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Distinct Patterns of Aging Effects on the Expression and Activity of Carboxylesterases in Rat Liver and Intestine

et al. 2013

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The age-associated alteration in expression levels of carboxylesterases (CESs) can affect both intestinal and hepatic first-pass metabolism after oral administration of xenobiotic esters such as prodrugs. In this study, the age-related expression of CES isozymes and hydrolase activities were simultaneously investigated in liver, jejunum, and ileum from 8-, 46-, and 90-week-old rats. Rat liver expresses three major CES1 isozymes, Hydrolase A, Hydrolase B, and Hydrolase C, as well as one minor CES1 (Egasyn) and three minor CES2 isozymes (RL4, AY034877, and D50580). The mRNA and protein levels of major hepatic CES1 isozymes were decreased in an age-dependent manner, while those of minor CESs were maintained in all age groups. The hepatic hydrolase activity for temocapril was decreased in an age-dependent manner, accompanied by downregulation of Hydrolase B/C mRNA, while age-independent hydrolysis of propranolol derivatives was observed in rat liver, due to the contribution of Egasyn. Rat small intestine expresses one major CES2 (RL4) and four minor CESs (Hydrolase B, Hydrolase C, Egasyn, and AY034877). Interestingly, the expression of RL4 was age-dependently increased in both jejunum and ileum, while minor isozymes showed a constant expression across a wide age range. The up-regulation of RL4 expression with aging led to an increase of intestinal hydrolase activities for temocapril and propranolol derivatives. Consequently, age-dependent changes in the expression of CES isozymes affect the hydrolysis of xenobiotics in both rat liver and small intestine.

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Section: Age-related Rat Hepatic and Intestinal Ces Expression 271mentioning

confidence: 83%

Section: Tablementioning

confidence: 98%

Distinct Patterns of Aging Effects on the Expression and Activity of Carboxylesterases in Rat Liver and Intestine

et al. 2013

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“…13,20–22 For example: Factors such as menopause and old age are risk factors for bone diseases in humans, but are poorly modelled in younger rodents and require careful consideration of translational biomarkers in older rodents to ensure cross-species comparability. 23–25 …”

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confidence: 99%

Does age matter? The impact of rodent age on study outcomes

et al. 2016

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Rodent models produce data which underpin biomedical research and non-clinical drug trials, but translation from rodents into successful clinical outcomes is often lacking. There is a growing body of evidence showing that improving experimental design is key to improving the predictive nature of rodent studies and reducing the number of animals used in research. Age, one important factor in experimental design, is often poorly reported and can be overlooked. The authors conducted a survey to assess the age used for a range of models, and the reasoning for age choice. From 297 respondents providing 611 responses, researchers reported using rodents most often in the 6–20 week age range regardless of the biology being studied. The age referred to as ‘adult’ by respondents varied between six and 20 weeks. Practical reasons for the choice of rodent age were frequently given, with increased cost associated with using older animals and maintenance of historical data comparability being two important limiting factors. These results highlight that choice of age is inconsistent across the research community and often not based on the development or cellular ageing of the system being studied. This could potentially result in decreased scientific validity and increased experimental variability. In some cases the use of older animals may be beneficial. Increased scientific rigour in the choice of the age of rodent may increase the translation of rodent models to humans.

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“…The small intestine is an important site of first-pass metabolism of numerous drugs, food components, and toxic xenobiotics. However, there is not much information available about age-dependent changes of intestinal biotransformation pathways (19). …”

Section: Expression Of Cyp In the Intestinementioning

confidence: 99%

“…However, it must be noted that there is a group of ultra-rapid metabolizers associated with CYP2D6, which results from gene amplification (9). Moreover, it seems that the activity of CYP complex in rat small intestine was not decreased by the aging process, so the high rate of oxidative metabolic reactions in intestinal mucosa can be maintained till the advanced life stage (19). …”

Section: Expression Of Cyp In the Intestinementioning

confidence: 99%

Intestinal cytochromes P450 regulating the intestinal microbiota and its probiotic profile

Bezirtzoglou¹

2012

Microbial Ecology in Health & Disease

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Cytochromes P450 (CYPs) enzymes metabolize a large variety of xenobiotic substances. In this vein, a plethora of studies were conducted to investigate their role, as cytochromes are located in both liver and intestinal tissues. The P450 profile of the human intestine has not been fully characterized. Human intestine serves primarily as an absorptive organ for nutrients, although it has also the ability to metabolize drugs. CYPs are responsible for the majority of phase I drug metabolism reactions. CYP3A represents the major intestinal CYP (80%) followed by CYP2C9. CYP1A is expressed at high level in the duodenum, together with less abundant levels of CYP2C8-10 and CYP2D6. Cytochromes present a genetic polymorphism intra- or interindividual and intra- or interethnic. Changes in the pharmacokinetic profile of the drug are associated with increased toxicity due to reduced metabolism, altered efficacy of the drug, increased production of toxic metabolites, and adverse drug interaction. The high metabolic capacity of the intestinal flora is due to its enormous pool of enzymes, which catalyzes reactions in phase I and phase II drug metabolism. Compromised intestinal barrier conditions, when rupture of the intestinal integrity occurs, could increase passive paracellular absorption. It is clear that high microbial intestinal charge following intestinal disturbances, ageing, environment, or food-associated ailments leads to the microbial metabolism of a drug before absorption. The effect of certain bacteria having a benefic action on the intestinal ecosystem has been largely discussed during the past few years by many authors. The aim of the probiotic approach is to repair the deficiencies in the gut flora and establish a protective effect. There is a tentative multifactorial association of the CYP (P450) cytochrome role in the different diseases states, environmental toxic effects or chemical exposures and nutritional status.

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Age-related changes in the mRNA levels of CYP1A1, CYP2B1/2 and CYP3A1 isoforms in rat small intestine

Cited by 10 publications

References 44 publications

Distinct Patterns of Aging Effects on the Expression and Activity of Carboxylesterases in Rat Liver and Intestine

Distinct Patterns of Aging Effects on the Expression and Activity of Carboxylesterases in Rat Liver and Intestine

Does age matter? The impact of rodent age on study outcomes

Intestinal cytochromes P450 regulating the intestinal microbiota and its probiotic profile

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