The effect of chronic kidney disease on CYP2B expression and activity in male Wistar rats

Abstract

Chronic kidney disease ( CKD ) is characterized by progressive reduction in kidney function over time. CKD affects greater than 10% of the population and its incidence is on the rise due to the growing prevalence of its risk factors. Previous studies demonstrated CKD alters nonrenal clearance of drugs in addition to reducing renal clearance. We assessed the function and expression of hepatic CYP 2B enzymes using a rat model of CKD . CKD was induced in Wistar rats by supplementing their chow with adenine and confirmed through the detection of elevated uremic toxins in plasma. Liver enzymes AST and ALT were unchanged by the adenine diet. Bupropion was used as a probe substrate for hepatic CYP 2B function using rat liver microsomes. The resulting metabolite, hydroxy‐bupropion, and bupropion were quantified by ultra‐performance liquid chromatography coupled to time‐of‐flight mass spectrometry. Level of mRNA and protein were determined by RT ‐ PCR and Western blot, respectively. The results of our study demonstrate that CYP 2B1 is downregulated in a rat model of CKD . CYP 2B1 mRNA level was significantly decreased (88%, P < 0.001) in CKD relative to control. Similarly, maximal enzymatic velocity ( V max ) for CYP 2B was decreased by 46% in CKD relative to control ( P < 0.0001). Previous studies involving patients with CKD demonstrated altered bupropion pharmacokinetics compared to control. Hence, our results suggest that these alterations may be mediated by attenuated CYP 2B hepatic metabolism. This finding may partially explain the alterations in pharmacokinetics and nonrenal drug clearance frequently observed in patients with CKD.

Anatomical distribution and expression of CYP in humans: Neuropharmacological implications

“…Recent studies demonstrated that patients affected by CKD had relevant changes in the metabolism of multiple drugs in addition to reducing renal clearance. In a rat model of CKD, a study aimed at assessing the function and expression of CYP2B enzymes, found that CYP2B1mRNA levels were significantly decreased in CKD relative to control animals, confirming previous data on the metabolic renal changes in CKD (Kucey et al, 2019).…”

Investigation of N,N,N-Trimethyl-L-alanyl-L-proline Betaine (TMAP) as a Biomarker of Kidney Function

“…We induced CKD using the dietary adenine model in Wistar rats. 16 Analysis of rat plasma revealed a significant increase in TMAP concentration between control and 0.7% adenine diet CKD rats and between 0.5 and 0.7% adenine diet CKD rats. These data show that the production of TMAP in nonhuman mammals is also reflective of kidney function, suggesting it is a robust marker.…”

“…Studies in rodents are often used to model clinical conditions such as CKD or acute kidney injury. We induced CKD using the dietary adenine model in Wistar rats . Analysis of rat plasma revealed a significant increase in TMAP concentration between control and 0.7% adenine diet CKD rats and between 0.5 and 0.7% adenine diet CKD rats.…”

“…Animals in the two CKD groups received a diet supplemented with either 0.5 or 0.7% adenine for 5 weeks, followed by 3 weeks of control diet, as previously described. 16 Control animals were pair-fed standard rat chow.…”

Evaluation of Zuo-Gui Yin Decoction Effects on Six CYP450 Enzymes in Rats Using a Cocktail Method by UPLC-MS/MS

“…In SD rats, CYP2B is mainly present in the form of CYP2B1, while in humans, it is CYP2B6 that predominates [33]. The two enzymes share 97% sequence homology and very similar substrate specificity, with catalytic activity being the main difference between the two enzymes, usually higher for CYP2B1 [34]. CYP2C7 gene is associated with the CYP2C subfamily of the rats [35].…”