|Bolling, Bradley w.|
|Court, Michael h.|
|Blumberg, Jeffrey b.|
|Chen, C-y oliver s.|
Submitted to: Drug Metabolism and Disposition
Publication Type: Peer reviewed journal
Publication Acceptance Date: 5/2/2011
Publication Date: 5/4/2011
Citation: Bolling, B., Court, M., Blumberg, J., Chen, C. 2011. Microsomal quercetin glucuronidation in rat small intestine depends on age and segment. Drug Metabolism and Disposition. 39(8):1406-1414. Interpretive Summary: Less characterized nutrients in plant foods, e.g., quercetin as a flavonol, displays protective effects against chronic diseases in animal models and clinical trials through multiple mechanisms, e.g., antioxidation and anti-inflammation. Dietary or supplemental quercetin has a low absorption rate and is extensively modified via detoxification mechanisms in intestine and liver, e.g., glucuronidation, sulfation, and methylation. These modifications facilitate quercetin efflux back to intestinal lumen before its systematic distribution and play a role in its limited availability to tissues. However, the factors affecting the capacity of such modifications have not been fully understood. Thus, in this study, we characterized the impact of age on quercetin glucuronidation catalyzed by UDP-glucuronosyltransferase (UGT). UGT activity toward the flavonoid quercetin and UGT protein were characterized in 3 equidistant small intestine (SI) segments from 4, 12, 18, and 28 mo male F344 rats. We found glucuronidation activity toward quercetin in small intestine was increased with age. However, UGT protein was not consistently changed with age. Thus, we found that the capacity of quercetin modification catalyzed by the detoxification mechanism was increased with age.
Technical Abstract: UDP-glucuronosyltransferase (UGT) activity toward the flavonoid quercetin and UGT protein were characterized in 3 equidistant small intestine (SI) segments from 4, 12, 18, and 28 mo male F344 rats, n=8/age using villin to control for enterocyte content. SI microsomal intrinsic clearance of quercetin were increased 3- to 9-fold from 4 mo in the proximal and distal SI at 12 and 18 mo. Similarly, at 30 µM quercetin, SI microsomal glucuronidation activity was increased with age, 4.8- and 3.9-fold greater at 18 mo than 4 mo. Quercetin UGT regioselectivity was not changed by age. The distal SI preferentially catalyzed glucuronidation at the 7-position, whereas the proximal SI produced the greatest proportion of 4’- and 3’-conjugates. Enterocyte UGT content in different SI segments was not consistently changed with age. In the proximal SI, UGT1A increased 64 and 150 % at 12 and 18 mo and UGT1A1, UGT1A7, and UGT1A8 were also increased at 12 and 18 mo. However, age-related changes in expression were inconsistent in the medial and distal segments. Microsomal rates of quercetin glucuronidation and UGT expression were positively correlated with UGT1A1 content for all pooled samples (R = 0.467) and at each age (R= 0.538 to 0.598). UGT1A7 was positively correlated with total, 7-O- and 3-O- quercetin glucuronidation at 18 mo. Thus, age-related differences in UGT quercetin glucuronidation depend upon intestinal segment and are more pronounced in the proximal and distal segments, and may be partially related to UGT1A1 and UGT1A7 content.