Silymarin Protects against Acute Liver Injury Induced by Acetaminophen by Downregulating the Expression and Activity of the CYP2E1 Enzyme

Abstract

Previous studies have shown that silymarin protects against various types of drug-induced liver injury, but whether the protective mechanism of silymarin against acetaminophen-induced liver injury is related to the CYP2E1 enzyme remains unclear. In this study, we investigated the effect of silymarin on the activity and expression of CYP2E1 in vitro and in vivo. The results of in vitro studies showed that silymarin not only inhibited the activity of CYP2E1 in human and rat liver microsomes but also reduced the expression of CYP2E1 in HepG2 cells. In vivo studies showed that silymarin pretreatment significantly reduced the conversion of chlorzoxazone to its metabolite 6-OH-CLX and significantly increased the t1/2, area under the curve (AUC) and mean residence time (MRT) of chlorzoxazone. In addition, silymarin pretreatment significantly inhibited the upregulation of Cyp2e1 expression, reduced the production of 3-cysteinylacetaminophen trifluoroacetic acid salt (APAP-CYS), and restored the liver glutathione level. The results of our study show that silymarin plays an important protective role in the early stage of acetaminophen-induced acute liver injury by reducing the activity and expression of CYP2E1, reducing the generation of toxic metabolites, and alleviating liver injury.

Acetaminophen-induced liver injury: Molecular mechanism and treatments from natural products

“…Silymarin has been reported to act as an antioxidant by reducing free radical production and lipid peroxidation, function as a toxin blocker by inhibiting the binding of toxins to the hepatocyte cell membrane receptors ( Abenavoli et al, 2010 ), and reduce the superoxide and peroxynitrite content by its scavenger activity ( Papackova et al, 2018 ). Recent research has shown that silymarin reduces acute toxic liver injury caused by APAP by increasing hepatocyte proliferation, decreasing CYP2E1 activity and expression, and decreasing the production of toxic metabolites ( Elsayed Elgarawany et al, 2020 ; Ihedioha et al, 2020 ; Yang et al, 2022b ). Silibinin is the major active component of silymarin.…”

The hepatoprotective effect of 4-phenyltetrahydroquinolines on carbon tetrachloride induced hepatotoxicity in rats through autophagy inhibition

“…Regarding CYP2E1, a member of the cytochrome P450 superfamily that participates effectively in the conversion of CCl 4 into free radicals, silymarin demonstrates a noteworthy decrease in CYP2E1 levels [ 69 ]. This reduction in CYP2E1 levels led to a decrease in free radical production and, subsequently, mitigated the induction of liver injury [ 70 ].…”

Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction

“…Many other natural compounds such as silymarin, resveratrol, curcumin, and berberine have effectively prevented the progression of MASLD and MASH [ 363 , 364 ]. Some of these naturally occurring compounds function as antioxidants and inhibitors of CYP2E1 [ 365 – 367 ] to prevent ALD, MASLD, and DILI. In addition, many naturally occurring antioxidants, including resveratrol, quercetin, and curcumin, are known to activate sirtuins, Nrf2, and PGC1α to improve liver disease outcomes [ 85 , 138 , 139 , 363 , 364 , 368 ].…”