Abstract
BackgroundThis study was aimed to examine circadian variations of hepatic antioxidant components, including the Nrf2- pathway, the glutathione (GSH) system, antioxidant enzymes and metallothionein in mouse liver.Methods and ResultsAdult mice were housed in light- and temperature-controlled facilities for 2 weeks, and livers were collected every 4 h during the 24 h period. Total RNA was isolated, purified, and subjected to real-time RT-PCR analysis. Hepatic mRNA levels of Nrf2, Keap1, Nqo1 and Gclc were higher in the light-phase than the dark-phase, and were female-predominant. Hepatic GSH presented marked circadian fluctuations, along with glutathione S-transferases (GST-α1, GST-µ, GST-π) and glutathione peroxidase (GPx1). The expressions of GPx1, GST-µ and GST-π mRNA were also higher in females. Antioxidant enzymes Cu/Zn superoxide dismutase (Sod1), catalase (CAT), cyclooxygenase-2 (Cox-2) and heme oxygenase-1 (Ho-1) showed circadian rhythms, with higher expressions of Cox-2 and CAT in females. Metallothionein, a small non-enzymatic antioxidant protein, showed dramatic circadian variation in males, but higher expression in females. The circadian variations of the clock gene Brain and Muscle Arnt-like Protein-1(Bmal1), albumin site D-binding protein (Dbp), nuclear receptor Rev-Erbα (Nr1d1), period protein (Per1 and Per2) and cryptochrome 1(Cry1) were in agreement with the literature. Furthermore, acetaminophen hepatotoxicity is more severe when administered in the afternoon when hepatic GSH was lowest.ConclusionsCircadian variations and gender differences in transcript levels of antioxidant genes exist in mouse liver, which could affect body responses to oxidative stress at different times of the day.
Highlights
Mammals have developed an endogenous circadian clock located in the suprachiasmatic nucleus of the anterior hypothalamus that responds to the solar time [1]
Circadian variations and gender differences in transcript levels of antioxidant genes exist in mouse liver, which could affect body responses to oxidative stress at different times of the day
Circadian variations of clock gene mRNA in the liver of mice
Summary
Mammals have developed an endogenous circadian clock located in the suprachiasmatic nucleus of the anterior hypothalamus that responds to the solar time [1]. The complexity of tissue- and day-time specific regulation of thousands of clock controlled genes involves many transcriptional regulators [6]. Circadian rhythms control myriads of physiological processes, including the production of reactive oxygen species (ROS) and its elimination, redo-sensitive gene activation and depression [7]. Endogenous circadian and exogenously driven daily rhythms include antioxidant enzymes and low molecular weight antioxidants such as glutathione [8]. Circadian variation of hepatic GSH-S transferase (GST) activity is evident in rodents [11]. This study was aimed to examine circadian variations of hepatic antioxidant components, including the Nrf2pathway, the glutathione (GSH) system, antioxidant enzymes and metallothionein in mouse liver
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