Effect of the Acute Phase Response Induced by Endotoxin Administration on the Expression and Activity of UGT Isoforms in Rats

Khalid   M.   Alkharfy; Samuel   M.   Poloyac; Mario      Congiu; Paul   V.   Desmond; Reginald   F.   Frye

doi:10.2174/187231208786734085

Abstract

To evaluate the effect of endotoxin administration on the glucuronidation of multiple substrates in a rat model. In addition, the effect of endotoxin treatment on selected UGT mRNA levels in the liver and the kidney was also investigated. Male Sprague-Dawley rats (n= 6) received endotoxin (1.6 mg/kg) by intraperitoneal injection. The animals were sacrificed at 6, 12, 24, 48 hr after treatment, and the liver and the kidneys were harvested. Glucuronidation of various substrates (i.e., acetaminophen, estradiol, testosterone, and morphine) was evaluated using prepared tissue microsomes. Real- Time PCR was used to determine mRNA levels of UGT1A1, 1A6, 2B1, and 2B3 in the harvested organs. UGT1A and UGT2B family isoforms were differentially affected by endotoxin treatment. The greatest reduction in glucuronide formation was observed for estradiol-17-glucuronide (-37%) in hepatic microsomes 48 hr after endotoxin administration. Estradiol- 3-glucuronide formation was reduced in liver microsomes (466.3±71.5 pmol/min/mg vs. 346.9±23.2 pmol/min/mg, p < 0.05) but was not significantly altered in the kidney. Similarly, acetaminophen glucuronide formation was decreased in liver but not kidney microsomes. Significant reductions in glucuronide formation were also observed for morphine (-26%) and testosterone (-30%) in septic rats compared to controls. Endotoxin administration was associated with a timedependent decrease in UGT1A1, UGT1A6, UGT2B1, and UGT2B3 mRNA levels in liver and kidney tissues. These findings demonstrate that both mRNA and activity of UGT isoforms in rats are decreased following endotoxin treatment, although tissue specific effects do also exist.

Keywords: Endotoxin, LPS, acute phase response, glucuronidation, UGT

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