The use of precision-cut liver slices from male Wistar rats as a tool to study age related changes in CYP3A induction and in formation of paracetamol conjugates

Wauthier, Val erie; Verbeeck, Roger K.; Calderón, Pedro Buc

doi:10.1016/j.tiv.2004.04.013

Cited by 12 publications

(5 citation statements)

References 39 publications

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“…Similar to our findings 2 other studies using RT-PCR noted a decrease in Cyp3a3 (Wauthier et al, 2004a;Peng et al, 2005) with age in male Wistar rats. It is unclear whether Cyp3a3 behaves differently in Sprague-Dawley rats or whether the radioactive probe technology lacked the sensitivity to detect an age-related decline in Cyp3a3 (Agrawal and Shapiro, 2003).…”

Section: Discussionsupporting

confidence: 93%

Hepatic Transcript Levels for Genes Coding for Enzymes Associated with Xenobiotic Metabolism are Altered with Age

Mori

Blackshear

Lobenhofer³

et al. 2007

Toxicol Pathol

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Metabolism studies are crucial for data interpretation from rodent toxicity and carcinogenicity studies. Metabolism studies are usually conducted in 6 to 8 week old rodents. Long-term studies often continue beyond 100 weeks of age. The potential for age-related changes in transcript levels of genes encoding for enzymes associated with metabolism was evaluated in the liver of male F344/N rats at 32, 58, and 84 weeks of age. Differential expression was found between the young and old rats for genes whose products are involved in both phase I and phase II metabolic pathways. Thirteen cytochrome P450 genes from CYP families 1-3 showed alterations in expression in the older rats. A marked age-related decrease in expression was found for 4 members of the Cyp3a family that are critical for drug metabolism in the rat. Immunohistochemical results confirmed a significant decrease in Cyp3a2 and Cyp2c11 protein levels with age. This indicates that the metabolic capacity of male rats changes throughout a long-term study. Conducting multiple hepatic microarray analyses during the conduct of a long-term study can provide a global view of potential metabolic changes that might occur. Alterations that are considered crucial to the interpretation of long-term study results could then be confirmed by subsequent metabolic studies.

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Section: Discussionsupporting

confidence: 93%

Hepatic Transcript Levels for Genes Coding for Enzymes Associated with Xenobiotic Metabolism are Altered with Age

Mori

Blackshear

Lobenhofer³

et al. 2007

Toxicol Pathol

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“…trans-activation studies [51] and by studies using HNF1α deficient mice, where a drastic decrease of CYP2E1 expression was observed [52]. Since a strong increase (154 %) in the amount of HNF1α mRNA is observed in senescent male rats [47], the increase of CYP2E1 expression in senescent rats may be related to the age-related increase of HNF1α.…”

Section: Effect Of Ageing On Cyps In Ratsmentioning

confidence: 97%

The Effect of Ageing on Cytochrome P450 Enzymes: Consequences for Drug Biotransformation in the Elderly

Wauthier¹,

Verbeeck

Calderón

2007

CMC

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Abstract:Ageing is an aggravating factor leading to alterations in the biotransformation of drugs, and therefore their therapeutic efficacy and safety. In this review we discuss the influence of ageing on drug metabolizing enzymes in male Wistar rats. We report that drug metabolizing enzymes can be affected by ageing either by post-translational modifications or by transcriptional modifications. The post-translational modifications could be due to an increase of oxidative stress during ageing. Although it is now well established that transcriptional modifications are due to a change in the GH secretion profile in senescent rats, the intracellular mechanisms underlying these modifications are still unclear. In addition to the strong decrease in the activity of the main CYPs of male rats, we discuss the potential consequences on human drug metabolism in the elderly.

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“…In this light, the modified CYP expression patterns observed in pregnancy, at different phases of the estrous cycle ( 137 , 138 ), in menopause or in subjects following hormonal replacement therapy ( 137 , 138 ) and in diabetes could be explained ( 102 ). The age-related alterations in the hepatic CYP expression pattern may also take place at transcriptional level and are often associated with oxidative stress and HNF1α levels, factors that are induced during the metabolic biotransformation of drugs at Phase I ( 102 , 118 , 139 , 140 ).…”

Section: Age-related Modifications In the Cyp-catalyzed Drug Metabolismmentioning

confidence: 99%

Age-related modifications in CYP-dependent drug metabolism: role of stress

Konstandi¹,

Johnson²

2023

Front. Endocrinol.

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Accumulating clinical evidence indicates extensive inter-individual variations in the effectiveness and adverse effects of standard treatment protocols, which are largely attributed to the multifactorial regulation of the hepatic CYP-dependent drug metabolism that is connected with either transcriptional or post-translational modifications. Age and stress belong to the most important factors in CYP gene regulation. Alterations in neuroendocrine responses to stress, which are associated with modified hypothalamo-pituitary-adrenal axis function, usually accompany ageing. In this light, ageing followed by a decline of the functional integrity of organs, including liver, a failure in preserving homeostasis under stress, increased morbidity and susceptibility to stress, among others, holds a determinant role in the CYP-catalyzed drug metabolism and thus, in the outcome and toxicity of pharmacotherapy. Modifications in the drug metabolizing capacity of the liver with age have been reported and in particular, a decline in the activity of the main CYP isoforms in male senescent rats, indicating decreased metabolism and higher levels of the drug-substrates in their blood. These factors along with the restricted experience in the use of the most medicines in childhood and elderly, could explain at an extent the inter-individual variability in drug efficacy and toxicity outcomes, and underscore the necessity of designing the treatment protocols, accordingly.

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The use of precision-cut liver slices from male Wistar rats as a tool to study age related changes in CYP3A induction and in formation of paracetamol conjugates

Cited by 12 publications

References 39 publications

Hepatic Transcript Levels for Genes Coding for Enzymes Associated with Xenobiotic Metabolism are Altered with Age

Hepatic Transcript Levels for Genes Coding for Enzymes Associated with Xenobiotic Metabolism are Altered with Age

The Effect of Ageing on Cytochrome P450 Enzymes: Consequences for Drug Biotransformation in the Elderly

Age-related modifications in CYP-dependent drug metabolism: role of stress

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