Effects of silver nanoparticles on rat hepatic cytochrome P450 enzyme activity

Abstract

Silver nanoparticles (AgNPs) are increasingly used in various products and consequentially the potential adverse effects associated with exposure to them are of concern. This study investigated the effects of AgNPs on the hepatic drug-metabolizing enzymes of the cytochrome P450 (CYP) families 1, 2 and 3, using both in vitro and in vivo biological assays. AgNPs were orally administered to Sprague-Dawley rats at various concentrations (0-1000 mg/kg body weight/day) for 2 weeks. No effect was found on the plasma levels of ALT, AST and ALP in all treated rat groups, and no significant change in the activities of CYP1A, CYP2C, CYP2D, CYP2E1 and CYP3A was observed for all tested AgNP doses. The results correlated with the observation that no AgNPs were detected in the liver sections of the tested rats. However, the in vitro system using rat liver microsomes demonstrated a strong inhibition of CYP2C (IC(50) = 28 µg/mL) and CYP2D (IC(50) = 23 µg/mL) activities, but not of CYP1A, CYP2E1 and CYP3A activities (IC(50) > 100 µg/mL) at concentrations up to 100 µg/mL of AgNPs. The inhibitory effect of AgNPs on these CYPs indicates the possibility of the AgNP-drug interaction when co-administered with some medicines and this may cause adverse effects to patients.

The Effect of Silver Nanoparticles on the Biochemical Parameters of Liver Function in Serum, and the Expression of Caspase-3 in the Liver Tissues of Male Rats

“…These findings suggest that Ag-NPs at these concentrations and durations of exposure did not cause any significant dysfunction in rat liver cells. Consistent with our study, Kulthong reported that oral administration of 180-nm Ag-NPs at doses of 50, 100, 250, 500, and 1000 mg/kg/day for two weeks did not significantly alter the serum ALT or AST levels (27). Elevated ALP and plasma cholesterol, dilatation of the central vein and bile duct, and hyperplasia were found in rats after oral administration of 60-nm Ag-NPs at more than 300 mg/kg/day for 28 days (29).…”

“…According to the findings, this difference between the biochemistry parameters and expression of caspase-3 may be because activation of caspases happens only transiently in the early apoptotic stages (27), without yet affecting liver function.…”

“…In vivo studies have been used for different routes of exposure to Ag-NPs, including intravenous, oral, inhalation, and intraperitoneal administration (17). Since a large number of silver nanoproducts are currently available in the food and beverage category (27), we used the oral route in our experiment. Most orally administered nanoparticulate silver has been described to be deposited in the liver, the major organ of detoxification (28).…”

“…Park et al in a 28-day oral toxicity study using 42-nm Ag-NPs with concentrations of 0.25 mg/kg, 0.5 mg/kg, and 1 mg/kg in mice, showed that the serum levels of ALP and AST were considerably increased (17). These discrepancies in toxicology studies are due to variations in the size of Ag-NPs that are used (31) and the duration of exposure (27). In the experiment carried out in mice with oral administration of 1 mg/kg of Ag-NPs for 14 days, it was observed that Ag-NPs at sizes of < 100 nm were spread throughout the brain, lung, liver, kidney, and testis, while large-sized Ag-NPs (323 nm) were not detected in those tissues (17).…”

Perturbation of physiological systems by nanoparticles

“…312 This pilot research only provides an indication of nanoparticles' effects on the metabolizing capability of the liver; it is possible that in vivo, the effects of silver nanoparticles on CYP enzymes are mitigated by additional protective mechanisms. The effects of nanoparticles on other functions, such as the secretion of bile, the synthesis of glucose and fatty acids, and blood iron content, are largely unknown.…”