Effects and Mechanism of Nano-Copper Exposure on Hepatic Cytochrome P450 Enzymes in Rats

Abstract

Although nano-copper is currently used extensively, the adverse effects on liver cytochrome P450 (CYP450) enzymes after oral exposure are not clear. In this study, we determined the effects and mechanisms of action of nano- and micro-copper on the expression and activity of CYP450 enzymes in rat liver. Rats were orally exposed to micro-copper (400 mg/kg), Cu ion (100 mg/kg), or nano-copper (100, 200 and 400 mg/kg) daily for seven consecutive days. Histopathological, inflammatory and oxidative stress were measured in the livers of all rats. The mRNA levels and activity of CYP450 enzymes, as well as the mRNA levels of select nuclear receptors, were determined. Exposure to nano-copper (400 mg/kg) induced significant oxidative stress and inflammation relative to the controls, indicated by increased levels of interleukin (IL)-2, IL-6, interferon (IFN)-γ, macrophage inflammatory protein (MIP-1), total antioxidant capacity (T-AOC), malondialdehyde (MDA), inducible nitric oxide synthase (iNOS) and nitric oxide (NO) after exposure. The levels of mRNA expression of pregnane X receptor (PXR), constitutive androstane receptor (CAR) and aryl hydrocarbon receptor (AHR) were significantly decreased in 400 mg/kg nano-copper treated rats. Nano-copper activated the expression of the NF-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT)3 signaling pathways. Nano-copper decreased the mRNA expression and activity of CYP 1A2, 2C11, 2D6, 2E1 and 3A4 in a dose-dependent manner. The adverse effects of micro-copper are less severe than those of nano-copper on the CYP450 enzymes of rats after oral exposure. Ingestion of large amounts of nano-copper in animals severely affects the drug metabolism of the liver by inhibiting the expression of various CYP450 enzymes, which increases the risk of drug-drug interactions in animals.

Dietary supplementation with copper nanoparticles influences the markers of oxidative stress and modulates vasodilation of thoracic arteries in young Wistar rats

“…However participation of 20-HETE derivate has been already ruled out. It's worth mentioning that an oral exposure to nano Cu is able to affect drug metabolism by inhibiting the expression of various CYP450 enzymes in the liver [5].…”

“…Once entering circulation, NPs interact with the endothelium and induce nitric oxide (NO) signaling impairment. Oxidative stress and inflammatory response is the mechanism of metal NPs [4,5].…”

All Roads Lead to the Liver: Metal Nanoparticles and Their Implications for Liver Health

“…[100] Copper NPs (80 nm) were found to inhibit the expression and activity of CYP1A2, CYP2C11, CYP2D6, CYP2E1, and CYP3A4 in rats. [56] Interestingly, nanosized copper particles were found to have a greater effect on CYP activity and transcript abundance compared to microsized copper particles (1 µm), demonstrating that this effect is size-dependent. [56] The transcriptional activity of CYPs involved in xenobiotic detoxification is regulated primarily by the pregnane X receptor (PXR), the constitutive androstane receptor (CAR), and the aryl hydrocarbon receptor (AhR).…”

“…[56] Interestingly, nanosized copper particles were found to have a greater effect on CYP activity and transcript abundance compared to microsized copper particles (1 µm), demonstrating that this effect is size-dependent. [56] The transcriptional activity of CYPs involved in xenobiotic detoxification is regulated primarily by the pregnane X receptor (PXR), the constitutive androstane receptor (CAR), and the aryl hydrocarbon receptor (AhR). All three transcription factors were significantly downregulated in copper NP-dosed rats, suggesting a transcriptional dysregulation reason for reduced CYP expression.…”

“…[55] Copper NPs were found to increase cytokine and chemokine levels (IL-2, IL-6, IFN-γ, and macrophage inflammatory protein-1), leading to increased liver injury through inflammation. [56] Silicon dioxide NPs (15 nm) were found to contribute to liver injury through increasing intracellular ROS levels in rat primary Kupffer cells, resulting in increased TNF-α, nitric oxide, and ROS expression. [57,58] Rats injected with silicon dioxide NPs (15 nm) showed greater immune cell proliferation and inflammatory response, potentially due to increased phagocytosis and activation by Kupffer cells.…”