Abstract
This study was aimed to clarify the effect of honokiol (Hon) on the activity of Cytochrome P450 (CYP450) enzymes, and the level of mRNA expression of liver and kidney transporters in type 2 diabetic rats induced by high-fat diet and strepotozotocin. Rats were randomly divided into normal control (NC) group, diabetic control (DC) group and Hon groups (n = 6). The activities of hepatic CYP1A2, CYP2E1, CYP2C, CYP2B, CYP3A and CYP4A, and the mRNA expression levels of hepatic and renal transporters, were determined. Compared to the NC group, the activities of CYP1A2, CYP2E1, CYP4A and CYP2C in DC group were increased by 2.36-, 2.10-, 2.55- and 1.86-fold, respectively. The mRNA expression levels of hepatic Oat2, Oatp2b1 and Oatp1a5, and renal Oct1, Octn2, Oatp2b1 and Oatp1a5, were significantly down-regulated, while the mRNA expression levels of hepatic Octn2, Oatp3a1, Oatp1a1 and Mdr2, and renal Oat2, Mrp4 and Bcrp, were significantly upregulated. Compared to the DC group, Hon treatment significantly inhibited the activity of hepatic CYP2E1, CYP4A, 3A and CYP1A2 by 45.6%, 29.2%, 22.7% and 20.7% in Hon high dose group, respectively. Moreover, Hon treatment significantly inhibited the mRNA expression levels of renal Bcrp and Mrp4 by 2.63-fold and 1.54-fold, while significantly upregulated the mRNA expression levels of hepatic Oat2 and Oatp2b1 by 1.52-fold and 1.54-fold in Hon high dose group, respectively. The results suggested that under the diabetes condition, the changes of CYP450 activity and transporter expression inevitably interfere the normal transport, metabolism and efficacy of drugs. The present work firstly reported that Hon treatment ameliorated the abnormal change of hepatic CYP activity (including CYP2E1, CYP4A and CYP1A2) and the transporter mRNA expression (including hepatic Oat2 and Oatp2b1, renal Bcrp and Mrp4) in type 2 diabetic rats induced by high-fat diet and strepotozotocin, which are associated with the occurrence and development of diabetes.
Highlights
With the improvement of living conditions, changes of diet structure and life style as well as the aggravation of aging, the incidence of diabetes increases rapidly in global, which makes diabetes become the third chronic disease severely threatened people’s health after tumor and cardiovascular disease
Our present work found that except the activities of hepatic CYP2B and 3A, the activities of hepatic CYP1A2, 2E1, 2C and 4A in the diabetic control (DC) rats were all increased significantly as compared with those in the normal control (NC) rats, suggesting that in the state of diabetes, the metabolic clearance of liver on the substrate drugs of CYP1A2, 2E1, 3C and 4A should be increased, which might affect the therapeutic action of drugs
After 8-week administration of Hon, the activity of hepatic CYP1A2, 2E1, 2C and 4A in the DC rats were dose-dependently inhibited while no obvious effect was observed for the hepatic CYP2B activity and only a significant inhibition for the hepatic CYP3A activity in the high dose of Hon
Summary
With the improvement of living conditions, changes of diet structure and life style as well as the aggravation of aging, the incidence of diabetes increases rapidly in global, which makes diabetes become the third chronic disease severely threatened people’s health after tumor and cardiovascular disease. The transport protein is a large class of membrane proteins that mediate the exchange of chemical substances and signal inside and outside the biofilm They are the most important factors that influence the pharmacokinetic process of drugs. Studies showed that the protein expression level and enzyme activity of CYP3A in T2DM rats induced by high-fat diet and streptozotocin were upregulated [5]. The mRNA expression level of hepatic CYP 1a2 was up-regulated in New Zealand Obesity mice [10]. In ob/ob mice, the mRNA and protein expression levels of hepatic Oatp1a1 as well as renal Oatp1a1mRNA expression levels were down-regulated, and the expression of breast cancer resistance protein (Bcrp) and Oat in kidney of rats with T2DM were upregulated [14]. The risk assessment of metabolic interaction in combined medication is of great importance, especially for the patients with diabetic complications
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