Dietary supplementation with quercetin alleviates fescue toxisis-induced cardiovascular toxicity by modulating detoxification enzymes through the AHR/NRF2/ABCC1 signaling pathways

Quercetin is considered a natural supplement product for its antioxidant, anti-inflammatory and contributes to cardiovascular protection. “Fescue toxicosis” is caused by the consumption of endophyte-positive tall fescue, negatively affecting the livestock cardiovascular system. The present study was to elaborate the protective mechanisms of quercetin against fescue toxicosis-induced cardiovascular toxicity. Twenty-four Dorper sheep were divided into four groups (n = 6). The groups included the E−,Q-group as the control group, fed endophyte-free fescue seed. The E+,Q-group was fed endophyte-positive fescue seed, while the E+,Q+ group received endophyte-positive fescue seed along with 4 mg of quercetin per kilogram of feed. The E−,Q+ group was fed endophyte-free fescue seed along with 4 mg of quercetin per kilogram of feed. The dietary regimens were maintained for a duration of 6 weeks. This study illustrated that quercetin effectively attenuated histological damage to the cardiovascular system and mitigated the increase in white cell counts. However, quercetin did not exert a significant impact on lowering serum prolactin levels. The compound demonstrated regulatory effects on Phase I detoxification enzymes, specifically cytochrome P450 (CYP450) family 1, 2, 3 (CYP1, CYP2, CYP3), by modulating the activity of nuclear receptors aryl hydrocarbon receptor (AHR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR). Furthermore, quercetin exhibited regulatory influence on nuclear factor erythroid 2-related factor 2 (NRF2), resulting in a substantial upregulation of antioxidant genes, notably NAD(P)H quinone dehydrogenase 1 (NQO1), heme oxygenase 1 (HO-1), and glutathione s-transferase (GST), among others. Additionally, quercetin significantly enhanced the mRNA expression of ATP binding cassette transporters, specifically ATP binding cassette subfamily C member 1 (ABCC1) and ATP binding cassette subfamily B member 1 (ABCB1). The study revealed that quercetin modulates the expression of detoxification metabolic enzymes by influencing AHR/NRF2/ABCC1, thereby attenuating the cardiovascular toxicity caused by fescue toxicosis. [Display omitted] •Quercetin attenuated fescue toxicosis-cardiovascular morphological lesions and leukocytosis.•Quercetin relieved the homeostasis of CYP450 enzymes disturbance by regulating NRs.•Quercetin alleviated reduction in phase II detoxification enzymes expression.•Quercetin mitigated the inhibition of the expression o