title: 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.
authors.affiliation: Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: T K
authors.initials: TK
authors.lastname: Motawi
authors.forename: Z A
authors.initials: ZA
authors.lastname: Teleb
authors.forename: N A
authors.initials: NA
authors.lastname: El-Boghdady
authors.forename: S A
authors.initials: SA
authors.lastname: Ibrahim
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000924:Anticholesteremic Agents / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D053938:DNA Fragmentation; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D005260:Female; D044950:Flavanones / Q000494:pharmacology / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008315:Malondialdehyde / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000633:toxicity*; D013482:Superoxide Dismutase / Q000097:blood
chemical_list: D000924:Anticholesteremic Agents; D000975:Antioxidants; D044950:Flavanones; D008315:Malondialdehyde; D019821:Simvastatin; D019392:Cytochrome P-450 CYP2E1; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D013482:Superoxide Dismutase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; C005273:naringenin