Age‐related changes in hepatic expression and activity of drug metabolizing enzymes in male wild‐type and breast cancer resistance protein knockout mice

Abstract

This study aimed to reveal age-related changes in the expression and activity of seven hepatic drug metabolizing enzymes (DMEs) in male wild-type and breast cancer resistance protein knockout (Bcrp1 ) FVB mice. The protein expression of four cytochrome P450 (Cyps) (Cyp3a11, 2d22, 2e1, and 1a2), and three UDP-glucuronosyltransferases (Ugts) (Ugt1a1, 1a6a, and 1a9) in liver microsomes of wild-type and Bcrp1 FVB mice at different ages were determined using a validated ultra high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method. The activities and mRNA levels of these DMEs were measured using the probe substrates method and real-time PCR, respectively. In the liver of wild-type FVB mice, Cyp3a11, 2d22, 2e1, 1a2, Ugt1a1, and 1a6a displayed maximum protein levels at 6-9 weeks of age. Cyp1a2, Ugt1a1, 1a6a, and 1a9 showed maximum activities at 6-9 weeks of age, whereas Cyp3a11, 2d22, and 2e1 showed maximum activities in 1-3-week-old mice. Additionally, most of the DMEs showed maximum mRNA levels in 17-week-old mice liver. Compared with wild-type FVB mice, the protein levels of these DMEs showed no significant changes in Bcrp1 FVB mice liver. However, the activity of Cyp2e1 was increased and that of Cyp2d22 was decreased. In conclusion, the seven hepatic DMEs in FVB mice liver showed significant alterations in an isoform-specific manner with increased age. Although the protein levels of these DMEs showed no significant changes, the activities of Cyp2e1 and 2d22 were changed in Bcrp1 mice.

Pharmacokinetics, Tissue Distribution, Metabolism, and Excretion of Naringin in Aged Rats

“…Most naringin was sequentially moved with gastrointestinal peristalsis, hydrolyzed to naringenin, and absorbed by gastrointestinal tract to construct the second peak, leading to a slow absorption of naringenin. Compared with adult rats (Wang et al, 2014; Ni et al, 2016), the T max of naringenin was significantly delayed for about 3.5 h and the half washout time ( t 1/2 ) was prolonged for about 1.5 h. These differences probably resulted from age-related changes in the gastrointestinal tract (Corsonello et al, 2010) and hepatorenal function (Zheng et al, 2018), including the reduction of gastric emptying, gastrointestinal peristalsis, bowel surface area, and splanchnic blood flow. It is interesting to note that the C max and area under the plasma concentration-time curve (AUC) were relatively higher (about two times) than that observed in adult rats (Wen et al, 2014).…”

“…On the one hand, time extension of gastric emptying and gastrointestinal peristalsis may prolong the exposure time of naringin to gut and lead to a more complete absorption. On the other hand, metabolic and excretive elimination of naringin was likely to be weakened due to the decrease of splanchnic blood flow, cytochromes P450 activities (Zheng et al, 2018), and drug transporter expression (Joseph et al, 2015). These changes given rise to a higher exposure of naringin and naringenin in aged rats.…”

“…Benefited from the high sensitivity and resolution of UFLC-Q-TOF-MS/MS system, more flavonoid metabolites (including O -diglucuronides, O -disulfate, O -glucuronide- O -sulfates, O -glucoside -O -glucuronides, O -glucoside -O -sulfates of naringenin and hesperetin) and phenolic catabolites (mainly derivates of 3-(phenyl)-2-propenoic acid) were screened in the urine and feces samples collected from aged rats, comparing with reported data in adult rats (Wang et al, 2006; Liu et al, 2012). Although remarkable age-related decrease in uridine 5’-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferases) was observed in rats (Zheng et al, 2018), glucuronidation still plays an important role in the metabolism of naringin in aged rats, as well as sulfation.…”