Effect of simvastatin and naringenin coadministration on rat liver DNA fragmentation and cytochrome P450 activity: an in vivo and in vitro study

Abstract

This study was designed to assess the effect of naringenin (NRG) on simvastatin (SV)-induced hepatic damage in rat and to investigate the effects of these drugs on cytochrome P450 (CYP) 2E1 and 3A1/2 isoforms in order to evaluate the possibility of their coadministration. Hepatic damage in rat was induced by SV (20 and 40 mg/kg/day, po for 30 days). The protective effect of NRG (50 mg/kg/day, po) was identified by estimating liver functions and oxidative stress markers such as lipid peroxidation, reduced glutathione, superoxide dismutase, glutathion s-transferase, and catalase as well as protein profile. DNA fragmentation and histopathological study were carried out to confirm the hepatic damage. An in vitro study was conducted to further evaluate the effect of SV and/or NRG administration on the activities of two microsomal CYP isoenzymes including CYP2E1 and CYP3A1/2. SV exerted an oxidative stress which may contribute to the hepatotoxicity. Administration of NRG in combination with SV significantly improved the liver functions, state of oxidative stress, protein profile, DNA fragmentation, and the histopathological changes. SV and/or NRG have a potential to inhibit CYP3A1/2 and CYP2E1. This study concluded that concurrent administration of NRG with SV provided a protection of liver tissue against the SV-induced hepatic damage. The inhibition of CYP2E1 and CYP3A1/2 by the SV and NRG should be taken into account in order to adjust doses to avoid interaction between SV and NRG and adverse effects of SV.

Combination of carvacrol with simvastatin improves the lipid‐lowering efficacy and alleviates simvastatin side effects

“…Group ΙΙΙ received P407 as in group ΙΙ plus SIM (20 mg/kg/day), p.o. daily for 30 days . Group ΙV received P407 as in group ΙΙ plus CARV (50 mg/ kg/day), p.o., daily for 30 days, Group V received P407 as in group ΙΙ plus SIM as in group ΙΙΙ plus CARV as in group ΙV.…”

“…daily for 30 days. [20] Group IV received P407 as in group II plus CARV (50 mg/ kg/day), p.o., daily for 30 days, [21] Group V received P407 as in group II plus SIM as in group III plus CARV as in group IV.…”

The Genoprotective Role of Naringin

“…Models based on Boltzmann distribution indicate that above a specific concentration, naringin shows no antioxidative action on ssDNA. Probably, at high doses of naringin, oxidation of DNA might occur, which may be induced by the high concentration of this flavonoid [24][25][26]. Large quantities of naringin can cause breakage and cleavage of genetic material into less fragments, as ssDNA is surrounded by a sufficient number of naringin molecules placed across the deoxyribose-phosphate chain.…”

“…Large quantities of naringin can cause breakage and cleavage of genetic material into less fragments, as ssDNA is surrounded by a sufficient number of naringin molecules placed across the deoxyribose-phosphate chain. Such cleavage would result in oligonucleotide decay into smaller fragments, as numerous studies have reported [24][25][26]. However, this phenomenon is connected with the high reactivity of the superoxide form of naringenin, which is obtained as a product of the reaction between naringin and ROS.…”

Antioxidants in liver health

“…Similar findings was reported by Esmaeili et al [136] , they showed that naringenin was capable of attenuating CCl4-induced liver injury by downregulating TNF-α, iNOS and cyclooxigenase-2, both protein and mRNA, as well as by increasing Nfr2 and HO-1 expression. Motawi et al [137] suggested that naringenin could be another example of CYP2E1 inhibitor, they probed it, in rat liver microsomal assay in co-administration with simvastin, and such inhibition of CYP2E1 is another via to improve antioxidant defenses [137] . There are currently no studies available in human hepatic disorders [138] .…”