Diurnal Variation of Hepatic Antioxidant Gene Expression in Mice

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.

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

“…2a), results consistent with findings in peritoneal macrophages ( Supplementary Fig. 1a) and with the diurnal variation observed by Xu and colleagues in liver tissue 12 .…”

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

“…34 Circadian regulation of Nrf2 is controlled by BMAL/CLOCK transcription factors and mediates rhythmic control of GSH levels as well as diurnal variation in drug-induced toxicity. 35,36 It has been reported that age-dependent alterations in the reduced versus oxidized ratio of glutathione (GSH/GSSG) significantly affects the redox state of the tissues. 37 These studies, although not definitive, suggest that decreases in total GSH and/or reduced/oxidized ratio of GSH may be mediated, in large part, by the impaired activation of Nrf2 in aging.…”

Influence of Simvastatin Chronotherapy on Erythrocytes Nitric oxide Synthase Activity

“…Melatonin is involved in biological clock function and its secretion reaches peak value after midnight. It has direct antioxidant activity: up regulates antioxidant enzymes, enhances non-enzymatic antioxidants and modulates NO bioavailability (Chakravarty and Rizvi, 2011;Xu et al, 2012).…”

“…Additionally, diurnal fluctuations of antioxidant enzymes activity was documented in mammals including humans (Singh et al, 2005;Xu et al, 2012). The PON1 is one of antioxidant enzymes protecting against oxidative damage (Nezami et al, 2011).…”

“…Similarly, Kamal (2011) demonstrated that evening treatment of statin induced better antioxidant profile than morning dosing. Moreover, melatonin plays a role in upregulation of antioxidant enzymes such as reductases and peroxidases (Berra and Rizzo, 2009;Chakravarty and Rizvi, 2011;Xu et al, 2012). Similarly, PON1 has peroxidase activity, therefore it may be induced by melatonin.…”