Age-Related Differences in CYP3A Expression and Activity in the Rat Liver, Intestine, and Kidney

Warrington, Jill; Greenblatt, David J.; Moltke, Lisa L. von

doi:10.1124/jpet.103.061077

Cited by 59 publications

(56 citation statements)

References 34 publications

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“…These findings were consistent with a previous study in which Warrington et al (2004) noted no statistically significant age-dependent changes of CYP3A expression in the rat small intestine. A comparable stability was also observed by Wauthier et al (2004) in constitutive hepatic CYP3A mRNA content in 3-, 8-, 11-and 18-month-old rats.…”

Section: Discussionsupporting

confidence: 83%

“…These data do not correlate with our results concerning rat small intestine, where the CYP3A1 inducibility was highest in oldest, 28-month-old individuals. The differences between small intestine and liver in age-dependent CYP3A protein expression were also reported by other authors (Warrington et al 2004) who showed that in the liver of aged rats, a significant decrease in CYP3A occurred, whereas the intestinal expression of this isoform was unchanged. George et al (1995) observed that the level of hepatic CYP3A protein in human decreases during aging.…”

Section: Discussionsupporting

confidence: 64%

“…The aged, 28-month-old rats were characterized by the highest activity of both NADPH-CYP450 and NADH-cytochrome b 5 reductases. Nevertheless, Warrington et al (2004) suggested an age-dependent decline in NADPH-CYP450 reductase protein expression in the rat small intestine. However, it is proper to notice that this western blotting and immunohistochemical study did not concern the enzymatic activity of both reductases in the gut microsomal fraction.…”

Section: Discussionmentioning

confidence: 99%

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

Pałasz

Wiaderkiewicz

et al. 2011

Genes Nutr

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It has been established beyond doubt that, as well as the liver, 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. In the present paper, we evaluated the relationships between intestinal cytochrome P450 complex activity and the age of animals. The study was carried out on male Sprague-Dawley rats (n = 5) from 5 age series: 0.5-, 2-, 4-, 20-, and 28 months old. Animals at every age series were divided into 4 groups: control and three groups of rats treated with the CYP450 specific inducers: phenobarbital, b-naphtoflavone and dexamethasone, respectively. RNA was isolated from intestinal mucosa, and then standard RT-PCR was used for the analysis of CYP1A1, CYP2B1/2 and CYP3A1 mRNA expression. Additionally, the activities of NADPH-cytochrome P450 and NADH-cytochrome b 5 reductases in the microsomal fraction were biochemically estimated. The constitutive intestinal CYP1A1 mRNA expression changes during maturation and aging. Inducibility of CYP1A1 gene was evident in intestinal mucosa at 2-, 4-and 20-month-old rats. A similar pattern of changes was observed for CYP2B1/2 isoforms. CYP3A1 mRNA expression was not detected in small intestine of 2-week-old rats. In matured rats, constitutive intestinal CYP3A1 expression was low, although after induction, significant increases in CYP3A1 mRNA amount were noted in aged individuals. Intestinal activity of both analyzed reductases was lowest in immature rats and highest in 28-month-old animals. In conclusion, the activity of cytochrome P450 complex in rat small intestine was not decreased by the aging processes, so the high rate of oxidative metabolic reactions in intestinal mucosa can be maintained till the advanced life stage.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Pałasz

Wiaderkiewicz

et al. 2011

Genes Nutr

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“…Moreover, CYP2C11 and CYP3A2 expression has been shown to decrease with age. 39,40 Similarly, our study confirmed that long-term regular exercise could delay the age-related decreases in some CYPs and DMEs.…”

Section: Discussionsupporting

confidence: 73%

Expression Profiles of Cytochrome P450s Following Swimming Exercise in Aging Rats

Lee¹,

So²,

Kim³

et al. 2017

JOMH

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“…The subjects in our study were young adults and within a narrow age range (mean/ range, 21/18-24 years), while in most other studies the age of the subjects ranged from 25 to 65 years. Expression of enzymes (CYP3A) producing AFQ 1 has been reported to decrease with age by approximately 25-40% in both animals 29 and humans, 30,31 and consumption of foods rich in flavonoids (e.g., green tea) may enhance AFQ 1 formation by activating these enzymes. 32,33 AFQ 1 is produced from AFB 1 in the liver by the CYP3A4 pathway, while AFM 1 is exclusively produced by CYP1A2.…”

Section: Discussionmentioning

confidence: 99%

Fecal and urinary excretion of aflatoxin B₁ metabolites (AFQ₁, AFM₁ and AFB‐N⁷‐guanine) in young Chinese males

Mykkänen

Zhu

Salminen

et al. 2005

Intl Journal of Cancer

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Our study was designed to assess the fecal and urinary excretion of 3 aflatoxin B 1 (AFB 1 ) metabolites, aflatoxins M 1 (AFM 1 ) and Q 1 (AFQ 1 ) and aflatoxin B 1 -N 7 -guanine (AFB-N 7 -guanine) that are produced by the predominant forms of cytochrome P450 enzymes responsible for the biotransformation of AFB 1 . Fecal and urinary AFM 1 , AFQ 1 and urinary AFB-N 7 -guanine were assessed in 83 young Chinese males selected from a larger population (n = 300) based on detectable urinary AFM 1 . The concentration of fecal AFQ 1 (median 137 ng/g fresh weight, IQR 9.1 to 450) was approximately 60 times higher than that of AFM 1 (2.3 ng/g, IQR 0.0 to 7.3). In urine, the median AFQ 1 was 10.4 ng/ml (IQR 3.4 to 23.3), and the median AFM 1 and AFB-N 7 -guanine 0.04 ng/ml (IQR 0.01 to 0.33) and 0.38 ng/ml (IQR 0.0 to 2.15), respectively. A subgroup (n = 14) with hepatitis B virus (HBV) infection had significantly higher fecal concentrations of AFQ 1 ( p = 0.043) and AFM 1 ( p = 0.001) than those who were hepatitis B-virus antigen (HBsAg) negative, and the respective differences in urinary AFQ 1 and AFM 1 concentrations approached statistical significance ( p = 0.054, p = 0.138). Our study demonstrates that AFQ 1 is excreted in urine and feces at higher levels than AFM 1 , and feces are an important route of excretion of these AFB 1 metabolites. AFQ 1 should be further assessed for its predictive value as a marker for exposure and risk of dietary aflatoxins. The most serious health effect of dietary exposure to aflatoxins is hepatocellular carcinoma. The etiology of this disease also involves chronic infection with hepatitis B and C viruses (HBV and HCV), and a significant synergistic interaction between aflatoxin exposure and hepatitis B virus has been reported. 2,3After oral uptake AFB 1 is efficiently absorbed and metabolized prior to excretion by fecal and urinary routes (Fig. 1). Absorbed AFB 1 and its metabolites are excreted in urine, while elimination to feces is a route for both the unabsorbed AFB 1 and biliary excretion of metabolites formed from the absorbed toxin. Animal studies have shown that under normal conditions 50% of the orally administered dose of AFB 1 is quickly absorbed from the duodenal region of the small intestine 4 and enters the liver through the hepatic portal blood supply.5 AFB 1 is concentrated in the liver and to a lesser extent in kidney, 6 and it is also found in the mesenteric venous blood as free AFB 1 or its water-soluble metabolites.Members of the cytochrome P450 (CYP) enzyme family, CYP1A2, CYP3A4 and CYP2A6 have been shown to be responsible for the metabolism of the absorbed aflatoxins 7,8 (Fig. 1). These enzymes convert AFB 1 to its carcinogenic form, AFB-8,9-epoxide, which is covalently bound to DNA 9 and serum albumin, 10 forming aflatoxin B 1 -N 7 -guanine (AFB-N 7 -guanine) and lysine adducts, respectively. These enzymes also oxidize AFB 1 to various other derivatives, including aflatoxin M 1 (AFM 1 ), aflatoxin Q 1 (AFQ 1 ), aflatoxin P 1 as well as a reduced aflatoxin species...

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Age-Related Differences in CYP3A Expression and Activity in the Rat Liver, Intestine, and Kidney

Cited by 59 publications

References 34 publications

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

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

Expression Profiles of Cytochrome P450s Following Swimming Exercise in Aging Rats

Fecal and urinary excretion of aflatoxin B₁ metabolites (AFQ₁, AFM₁ and AFB‐N⁷‐guanine) in young Chinese males

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Age-Related Differences in CYP3A Expression and Activity in the Rat Liver, Intestine, and Kidney

Cited by 59 publications

References 34 publications

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

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

Expression Profiles of Cytochrome P450s Following Swimming Exercise in Aging Rats

Fecal and urinary excretion of aflatoxin B1 metabolites (AFQ1, AFM1 and AFB‐N7‐guanine) in young Chinese males

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Product

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Fecal and urinary excretion of aflatoxin B₁ metabolites (AFQ₁, AFM₁ and AFB‐N⁷‐guanine) in young Chinese males