Comparative Analysis of Selected UGT and SULT mRNA Expression in Non-Obese Rat Models of Metabolic Syndrome.

Background

Metabolic syndrome (MetS) is a cluster of risk factors increasing the likelihood of cardiovascular and metabolic diseases.

Objectives

This study investigated the relative mRNA expression of key hepatic and intestinal phase II drug-metabolising enzymes, specifically UDP-glycosyltransferases (UGTs) and sulfotransferases (SULTs), in four non-obese rat models of MetS characterised by different dominant traits: the hereditary hypertriglyceridaemic (HHTg) rat, spontaneously hypertensive rat (SHR), SHR-expressing transgenic human C-reactive protein (SHR-CRP) rat, and bilaterally ovariectomised female Wistar (W-OVX) rat, compared to Wistar controls.

Methods

Gene expression was quantified by RT-PCR with data normalised using the ΔΔCt method.

Results

Measurements showed significant model-specific differences, especially in the liver. HHTg rats exhibited significant hepatic suppression of Ugt1a9 (-90%) and undetectable Ugt2b transcripts, alongside compensatory upregulation of Sult1a1 (196%) and Sult1b1 (277%). The SHR model showed significant hepatic upregulation of Ugt1a1 (330%), Sult1a1 (266%), and Sult1b1 (328%). Chronic inflammation in SHR-CRP rats caused a significant decrease in hepatic Ugt1a1, whereas a significant induction occurred in the intestine. Oestrogen deprivation (W-OVX) led to significant downregulation of hepatic Ugt1a6 and Ugt1a9.

Conclusions

These findings highlight that the alterations in phase II metabolism strongly depend on the pathophysiological context, potentially affecting drug disposition in preclinical models.