EXPRESSION OF UDP-GLUCURONOSYLTRANSFERASE ISOFORM mRNAS DURING INFLAMMATION AND INFECTION IN MOUSE LIVER AND KIDNEY

Abstract

ABSTRACT:Inflammation or infection down-regulates the activity and expression of cytochrome P450 (P450) enzymes involved in hepatic drug clearance, possibly altering drug effectiveness and leading to toxicity. The regulation of UDP-glucuronosyltransferases (UGTs) in inflammation and infection is less well characterized. To determine the response of hepatic and renal UGTs during inflammation and infection, mice were administered either saline or 1 mg/kg lipopolysaccharide (LPS) (16 h), or Citrobacter rodentium by oral gavage (6 days). Hepatic mRNA expression of UGT1A1, 1A9, and 2B5 was similarly down-regulated after LPS exposure and C. rodentium infection, whereas UGT1A2 and 1A6 mRNAs were unchanged. Effects of C. rodentium infection did not require a functional Toll-like receptor 4. Conversely, renal UGT isoforms were relatively unaffected, except for UGT2B5 induction after LPS treatment. Regulation of UGTs during the inflammatory response exhibits similarities to and differences from regulation of P450s, and may be cytokinemediated.UDP-glucuronosyltransferases (UGTs) reside in the endoplasmic reticulum and catalyze the biotransformation of a variety of substrates (Wells et al., 2004). Addition of glucuronic acid by UGTs generally increases the water solubility of compounds for subsequent excretion in bile or urine. UGTs have multiple constitutive and inducible isoforms with overlapping substrate specificities, and are expressed in both hepatic and extrahepatic tissues (Wells et al., 2004).Inflammation and infection can alter drug metabolism in humans and rodents, resulting in significantly increased or decreased drug efficacy and potential toxicity. Both cytochrome P450 (P450) expression and metabolic activities in liver and extrahepatic tissues can be down-regulated during inflammation Renton, 2004). However, little is known regarding UGT activities during the inflammatory response. Because hepatic P450 metabolism is significantly suppressed during inflammation, hepatic glucuronidation may be similarly affected and may contribute to alterations in drug efficacy.Injection of bacterial lipopolysaccharide (LPS) is a widely used model of inflammation and is well characterized regarding its effects on basal and inducible hepatic P450 expression. Many in vivo effects of LPS-induced inflammation are due to proinflammatory cytokines, and these cytokines mimic the effects of LPS when injected in vivo or incubated with hepatocytes Renton, 2004). In contrast to P450s, very little data exist on UGT regulation during LPS-induced inflammation. Significant decreases in hepatic UGT activities were reported after LPS administration in rats and isolated perfused mouse liver (Chen et al., 1992;Banhegyi et al., 1995), but no effect on UGTs was found in mouse hepatocytes (Banhegyi et al., 1995). Glucuronidation was unchanged after injection of individual cytokines in rats (Chen et al., 1992), yet it was inhibited in isolated pig hepatocytes after cytokine administration (Monshouwer et al., 1996). Even less information exists regar...

Thioacetamide Intoxication Triggers Transcriptional Up-Regulation but Enzyme Inactivation of UDP-Glucuronosyltransferases

“…The references in the current literature concerning the transcriptional regulation of UGTs in liver injury are largely controversial. Some reports showed that most UGT isoforms were transcriptionally downregulated in the liver samples from humans with liver diseases, which was found to correlate with inflammation but not with fibrosis scores (Congiu et al, 2002), and from the liver samples of mice treated with lipopolysaccharides or bacterial infections (Richardson et al, 2006). However, another set of reports witnessed an up-regulation of most UGT isoforms in humans with cirrhosis (Debinski et al, 1995) and rat liver samples (Debinski et al, 1996), as well as in regenerated rat liver tissues after partial hepatectomy (Pellizzer et al, 1996).…”

“…UGT activities were found largely preserved in liver diseases, possibly because of the activation of latent UGT enzymes (Desmond et al, 1994), the increased expression in remaining viable cells (Debinski et al, 1995), and the increased contribution of extrahepatic UGTs (Omar et al, 1996). However, more recent studies focusing on the mRNA levels of individual UGT isoforms from clinical patients with liver diseases (Congiu et al, 2002) and mice with inflammation (Richardson et al, 2006) indicated downregulations of most UGT isoforms. The major limitation of previous studies concerning UGT regulation in liver injury is that the expression and enzyme activity of individual isoforms have not been concomitantly evaluated, resulting in inconsistencies across various studies with different measures.…”

Differences in the Disposition of Silymarin between Patients with Nonalcoholic Fatty Liver Disease and Chronic Hepatitis C

“…The simplest explanation is that the expression or activity of UGTs is decreased in NAFLD subjects. Nonalcoholic steatohepatitis, a specific subset of NAFLD, is characterized by hepatic steatosis and varying degrees of inflammation, which can lead to decreased UGT expression as has been observed in rodents (Richardson et al, 2006) and in human liver tissue (Congiu et al, 2002). Therefore, it is plausible that the major UGT isoforms involved in metabolism of silymarin may be lower in NAFLD subjects, resulting in higher plasma levels of parent flavonolignans and lower concentrations of conjugates.…”

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

“…The one demonstrated mechanism that is common in these conditions is, in part, oxidative stress (Kirby et al, 1994b;Chomarat et al, 1997;Nebert et al, 2000;Cheung et al, 2003;Gilmore et al, 2003;Gilmore and Kirby, 2004;Su and Ding, 2004;Weng et al, 2005;Chen and Siddiqui, 2007;Fisher et al, 2009;De-Oliveira et al, 2010). Furthermore, these conditions appear to be associated with increased serum bilirubin levels (Bonacini, 2004;Malaguarnera et al, 2005;Richardson et al, 2006b;Hansen, 2010). (Pellinen et al, 1993) Chloroform Anesthetic/Teflon (Camus et al, 1996) Cocaine Topical anesthetic (Pellinen et al, 1994a(Pellinen et al, , 1994b) Ethanol Fuel, beverage, and antiseptic (Lu et al, 2010) Phenobarbital Barbiturate and anticonvulsant (Hahnemann et al, 1992;Salonpää et al, 1994) Pyrazole Precursor for various medicines (Juvonen et al, 1985;Nichols and Kirby, 2008 (Cai et al, 2002) Buthionine sulfoximine Drug used in chemotherapy to reduce levels of glutathione (Gilmore et al, 2003) pregnenolone 16a-carbonitrile (PCN) Pregnane X receptor (PXR) agonist or antiglucocorticoid (Cai et al, 2002) Rifampicin Bactericidal antibiotics (Donato et al, 2000) Trans-4,5-dihydroxy-1,2-dithiane (DTTox) Intramolecular disulfide form of dithiothreitol; reducing agent (Gilmore and Kirby, 2004) (Montero et al, 1999) Bilirubin Bilirubin (BR) is the end product of heme catabolism, and heme is found in hemoglobin or other hemoproteins such as cytochromes, catalase, and a small pool of unbound free heme (Roy-Chowdhury et al, 2007).…”