Effect of normal aging on the activity of human hepatic cytochrome P450IIE1

Hunt, Christine M.; Strater, Sharon; Stave, Gregg M.

doi:10.1016/0006-2952(90)90470-6

Cited by 44 publications

(16 citation statements)

References 21 publications

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“…Indeed, several authors reported a loss of hepatic P450 activity (Rikans and Notley 1982;Rikans 1989;Imaoka et al 1991;George et al 1995;Warrington et al 2000;Sotaniemi et al 1997), whereas some others reported that its activity was unchanged during ageing (Schmucker and Wang 1981;Hunt et al 1990;Schmucker et al 1990). Most of these discrepancies are related to the experimental approach utilized by the different laboratories: namely, the animal models used, the time of observation, the isozyme studied and the specificity of the substrate used as a probe for enzymatic activity.…”

Section: Discussionmentioning

confidence: 94%

“…A number of human studies have demonstrated an age-related decline in the clearance of drugs undergoing biotransformation by cytochrome P450 (CYP) enzymes, but conflicting results are reported when using human liver microsomes. Indeed, total hepatic CYP content as well as some CYP activities are either decreased (George et al 1995;Sotaniemi et al 1997) or remain unchanged (Hunt et al 1990;Schmucker et al 1990). It must be underlined that both in vivo and in vitro human studies may be complicated by epigenetic factors such as disease, medications, diet and tobacco or alcohol use, as well as genetic factors (Warrington et al 2000).…”

Section: Introductionmentioning

confidence: 97%

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Age-related changes in the protein and mRNA levels of CYP2E1 and CYP3A isoforms as well as in their hepatic activities in Wistar rats. What role for oxidative stress?

Wauthier

Verbeeck

Calderón

2004

Archives of Toxicology

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Drug biotransformation and its therapeutic effect may be modified during ageing. Among different causative factors of ageing, the impairment of normal cellular functions by free radicals has been evoked as playing a critical role. The effect of age on the expression and activity of CYP2E1 and CYP3A was investigated in male Wistar rats of 3, 8, 11 and 18 months old. The total cytochrome P450 as well as the expression and the activity (midazolam oxidation) of CYP3A isoforms did not change until 18 months of age. Chlorzoxazone hydroxylation (CYP2E1 activity) increased from 3 to 8 months, remained constant between 8 and 11 months and then progressively decreased until 18 months. Interestingly, CYP2E1 microsomal protein followed the same enzyme activity profile from 3 to 8 months, but remained constant thereafter. The level of CYP2E1 mRNA did not change over the whole period. While the amount of proteins did not change after 8 months, their functionality may be affected by oxidative stress (increase in thiobarbituric acid reactive substances, decrease in reduced glutathione level). However, no changes in carbonyl protein content were observed. The decrease in CYP2E1 activity in rats after 11 months is most probably due to post-translational modifications of CYP2E1 proteins. Indeed, it may be correlated with an accumulation of oxidative damage. Since no change was observed in CYP3A activity or in their protein and mRNA content, it seems that such isoforms should be less affected by oxidative stress.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 97%

Age-related changes in the protein and mRNA levels of CYP2E1 and CYP3A isoforms as well as in their hepatic activities in Wistar rats. What role for oxidative stress?

Wauthier

Verbeeck

Calderón

2004

Archives of Toxicology

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“…This study included only adult subjects and therefore the established relationship of enzyme expression with age until adulthood (ontogeny) was not observed (Al Omari and Murry, 2007;Court, 2010). In adult subjects, age was reported to have little effect on the abundance and activity of cytochrome P450 (Hunt et al, 1990(Hunt et al, , 1992Schmucker et al, 1990;Shimada et al, 1994) and on the activity of UGT enzymes (Herd et al, 1991;Court, 2010). Analysis of reported metabolic ratios indicated a decline in metabolic activity that parallels the decline in renal function (Rostami-Hodjegan et al, 1999); however, liver size shrinkage as body size decreases with age (Polasek et al, 2013) may be a contributing factor.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous Quantification of the Abundance of Several Cytochrome P450 and Uridine 5′-Diphospho-Glucuronosyltransferase Enzymes in Human Liver Microsomes Using Multiplexed Targeted Proteomics

Achour

Russell

Barber

et al. 2014

Drug Metabolism and Disposition

152

196

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Cytochrome P450 (P450) and uridine 59-diphospho-glucuronosyltransferase (UGT) enzymes mediate a major proportion of phase I and phase II metabolism of xenobiotics. In vitro-in vivo extrapolation (IVIVE) of hepatic clearance in conjunction with physiologicallybased pharmacokinetics (PBPK) has become common practice in drug development. However, prediction of xenobiotic kinetics in virtual populations requires knowledge of both enzyme abundances and the extent to which these correlate. A multiplexed quantification concatemer (QconCAT) strategy was used in this study to quantify the expression of several P450 and UGT enzymes simultaneously and to establish correlations between various enzyme abundances in 24 individual liver samples (ages 27-66, 14 male ), expressed as mean 6 S.D. Previous reports of correlations in expression of various P450 (CYP3A4/CYP3A5*1/*3, CYP2C8/CYP2C9, and CYP3A4/CYP2B6) were confirmed. New correlations were demonstrated between UGTs [including UGT1A6/UGT1A9 (r s = 0.82, P < 0.0001) and UGT2B4/UGT2B15 (r s = 0.71, P < 0.0001)]. Expression of some P450 and UGT enzymes were shown to be correlated [including CYP1A2/UGT2B4 (r s = 0.67, P = 0.0002)]. The expression of CYP3A5 in individuals with *1/*3 genotype (n = 11) was higher than those with *3/*3 genotype (n = 10) (P < 0.0001). No significant effect of gender or history of smoking or alcohol use on enzyme expression was observed; however, expression of several enzymes declined with age. The correlation matrix produced for the first time by this study can be used to generate more realistic virtual populations with respect to abundance of various enzymes.

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“…Pro-inflammatory cytokines and acute-phase reactants are elevated in many patients with advanced cancer (Heys et al, 1998;Martin et al, 1999) and there is, therefore, the possibility that part of the inter-individual variability in drug clearance and toxicity could relate to the effects of these cytokines on CYP3A expression (Moreno et al, 1991;Craig et al, 1993;Chen et al, 1994;Muntane-Relat et al, 1995;Morgan, 1997;Pascussi et al, 2000). Further falls in CYP3A function may occur with age (Hunt et al, 1990) and reduced hepatic drug clearance may contribute to a greater risk of adverse events in elderly cancer patients (Yancik et al, 1998).…”

mentioning

confidence: 99%

Hepatic cytochrome P450 3A drug metabolism is reduced in cancer patients who have an acute-phase response

Rivory

Slaviero

Clarke³

2002

Br J Cancer

195

153

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Inflammatory disease states (infection, arthritis) are associated with reduced drug oxidation by the cytochrome P450 3A system. Many chemotherapy agents are metabolised through this pathway, and disease may therefore influence inter-individual differences in drug pharmacokinetics. The purpose of this study was to assess cytochrome P450 3A function in patients with advanced cancer, and its relation to the acute-phase response. We evaluated hepatic cytochrome P450 3A function in 40 patients with advanced cancer using the erythromycin breath test. Both the traditional C 20min measure and the recently proposed 1/T MAX values were estimated. The marker of acute-phase response, C-reactive protein and the pro-inflammatory cytokines IL-6, IL-1b, TNFa and IL-8 were measured in serum or plasma at baseline. Cancer patients with an acute phase response (C-reactive protein 410 mg l 71 , n=26) had reduced metabolism as measured with the erythromycin breath test 1/ T MAX (Kruskal -Wallis Anova, P=0.0062) as compared to controls (C-reactive protein 410 mg l 71 , n=14) . Indeed, metabolism was significantly associated with C-reactive protein over the whole concentration range of this acute-phase marker (r=70.64, Spearman Rank Correlation, P50.00001). C-reactive protein serum levels were significantly correlated with those of IL-6 (Spearman coefficient=0.58, P50.0003). The reduction in cytochrome P450 3A function with acute-phase reaction was independent of the tumour type and C-reactive protein elevation was associated with poor performance status. This indicates that the sub-group of cancer patients with significant acute-phase response have compromised drug metabolism, which may have implications for the safety of chemotherapy in this population.

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Effect of normal aging on the activity of human hepatic cytochrome P450IIE1

Cited by 44 publications

References 21 publications

Age-related changes in the protein and mRNA levels of CYP2E1 and CYP3A isoforms as well as in their hepatic activities in Wistar rats. What role for oxidative stress?

Age-related changes in the protein and mRNA levels of CYP2E1 and CYP3A isoforms as well as in their hepatic activities in Wistar rats. What role for oxidative stress?

Simultaneous Quantification of the Abundance of Several Cytochrome P450 and Uridine 5′-Diphospho-Glucuronosyltransferase Enzymes in Human Liver Microsomes Using Multiplexed Targeted Proteomics

Hepatic cytochrome P450 3A drug metabolism is reduced in cancer patients who have an acute-phase response

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