Metabolic Profiling and Investigation of the Modulatory Effect of L. Aerial Parts on Hepatic CYP3A4 and UGT2B7 Enzymes in Streptozotocin-Induced Diabetic Model

Overview

Journal Antioxidants (Basel)

Date 2023 Jan 21

PMID 36670981

Authors

Shahzad Kamran

Rukhsana Anwar

Afifa Noor

Muhammad Ihsan Ullah

Alaa A Bagalagel

Mohammed M Aldurdunji

Saiqa Ishtiaq

Affiliations

Soon will be listed here.

Abstract

Drug-metabolizing enzymes are either boosted or suppressed by diabetes mellitus. This research was designed to explore L. aerial parts' impact on CYP3A4 and UGT2B7 activity and their mRNA expression in diabetic rats. () dried powder was sequentially extracted with -hexane, chloroform, ethyl acetate, methanol, and water. The methanol extract and aqueous fraction presented the most significant potential to decrease the concentration of -hydroxyl midazolam, with 176.0 ± 0.85 mg/Kg and 182.9 ± 0.99 mg/Kg, respectively, compared to the streptozotocin (STZ)-induced diabetic group, reflecting the inhibition in CYP3A4 activity. The fold change in mRNA expression of CYP3A4 was decreased significantly by the methanol extract, and the aqueous fraction of estimated by 0.15 ± 0.002 and 0.16 ± 0.001, respectively, compared with the diabetic group. Morphine metabolism was significantly increased in rats treated with methanol extract and its aqueous fraction, displaying 93.4 ± 0.96 mg/Kg and 96.4 ± 1.27 mg/Kg, respectively, compared with the metabolism of morphine in the diabetic group, which highlights the induction of UGT2B7 activity. The fold change in mRNA expression of UGT2B7 was significantly increased by the methanol extract and the aqueous fraction, estimated at 8.14 ± 0.26 and 7.17 ± 0.23 respectively, compared to the diabetic group. Phytochemical analysis was performed using high-performance liquid chromatography (HPLC), where the methanol extract showed more flavonoids and phenolic compounds compared to the aqueous fraction of The obtained results were further consolidated by molecular docking studies, where quercetin showed the best fitting within the active pocket of CYP3A4, followed by gallic acid, displaying free binding energies (∆G) of -30.83 and -23.12 kcal/mol, respectively. Thus, could serve as a complementary medicine with standard anti-diabetic therapy that can modulate the activity of the drug-metabolizing enzymes.

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