Hepatic cytochrome P-450 reductase-null mice show reduced transcriptional response to quercetin and reveal physiological homeostasis between jejunum and liver

Abstract

P-450reductase-null mice show reduced transcriptional response to quercetin and reveal physiological homeostasis between jejunum and liver. Am J Physiol Gastrointest Liver Physiol 290: G63-G72, 2006. First published February 2, 2006 doi:10.1152/ajpgi.00565.2005.-Using mice deficient in hepatic cytochrome P-450 oxidoreductase (POR), which disables the liver cytochrome P-450 system, we examined the metabolism and biological response of the anticarcinogenic flavonoid, quercetin. Profiling circulating metabolites revealed similar profiles over 72 h in wild-type (WT) and POR-null (KO) mice, showing that hepatic P450 and reduced biliary secretion do not affect quercetin metabolism. Transcriptional profiling at 24 h revealed that two-to threefold more genes responded significantly to quercetin in WT compared with KO in the jejunum, ileum, colon, and liver, suggesting that hepatic P450s mediate many of the biological effects of quercetin, such as immune function, estrogen receptor signaling, and lipid, glutathione, purine, and amino acid metabolism, even though quercetin metabolism is not modified. The functional interpretation of expression data in response to quercetin (single dose of 7 mg/animal) revealed a molecular relationship between the liver and jejunum. In WT animals, amino acid and sterol metabolism was predominantly modulated in the liver, fatty acid metabolism response was shared between the liver and jejunum, and glutathione metabolism was modulated in the small intestine. In contrast, KO animals do not regulate amino acid metabolism in the liver or small intestine, they share the control of fatty acid metabolism between the liver and jejunum, and regulation of sterol metabolism is shifted from the liver to the jejunum and that of glutathione metabolism from the jejunum to the liver. This demonstrates that the quercetin-mediated regulation of these biological functions in extrahepatic tissues is dependent on the functionality of the liver POR. In conclusion, using a systems biology approach to explore the contribution of hepatic phase 1 detoxification on quercetin metabolism demonstrated the resiliency and adaptive capacity of a biological organism in dealing with a bioactive nutrient when faced with a tissue-specific molecular dysfunction.

Chronic quercetin exposure affects fatty acid catabolism in rat lung

“…However, the decrease in plasma fatty acid levels is consistent with the fact that quercetin modulates fatty acid metabolism in rats. Effects of quercetin on metabolism of energetic substrates were also reported by Mutch et al [27]. Using affymetrix gene chips and cytochrome P450 reductase knockout mice, they showed that after a short, 4-h exposure to a 0.62% quercetin diet, amino acid metabolism, lipid metabolism and glutathione metabolism pathways were altered in liver and intestines.…”

“…Using affymetrix gene chips and cytochrome P450 reductase knockout mice, they showed that after a short, 4-h exposure to a 0.62% quercetin diet, amino acid metabolism, lipid metabolism and glutathione metabolism pathways were altered in liver and intestines. Moreover, genetically eliminating the expression of the phase I enzyme did not alter quercetin metabolism itself, but altered the tissue-specific location of differentially regulated major metabolism pathways by quercetin [27]. Several other flavonoids have also been shown to interfere with the homeostasis of fat storage and fatty acid metabolism.…”

“…Only one study on quercetin has used an animal model in combination with large scale gene expression techniques. Mutch et al [27] showed that exposure of hepatic cytochrome-P450 oxidoreductase-knockout and wild-type mice to an acute high dose of quercetin (7 mg/mouse), induced alterations in several biological pathways in jejunum, colon and liver. Although metabolism of quercetin did not differ between wild-type and knockout mice, tissue-specific effects on amino acid metabolism, lipid metabolism, glutathione metabolism and antigen presentation were found [27].…”

Increasing skeletal muscle fatty acid transport protein 1 (FATP1) targets fatty acids to oxidation and does not predispose mice to diet-induced insulin resistance

“…Genetically altering lipid metabolism at the whole body level via ablation or overexpression of selected genes can influence metabolism in two different ways, either by directly altering energy supply and storage, and/or by altering signalling pathways that affect gene expression and protein content in an endocrine and exocrine manner, as highlighted by others (review) [18,19]. Therefore, interpretation of such experiments may be complex, as ablation of a gene in one tissue can affect metabolism in other tissues [20][21][22][23]. Since ablation of Fatp1 seems to reorganise lipid metabolism in various tissues [16], it is unclear whether the protection against diet-induced insulin resistance is attributable to ablation of Fatp1 in muscle or to adaptive alterations in lipid metabolism in other tissues.…”

Regulation of Intestinal Cytochrome P450 Expression by Hepatic Cytochrome P450: Possible Involvement of Fibroblast Growth Factor 15 and Impact on Systemic Drug Exposure

“…Two previous reports have dealt with the relationships between liver and intestine in mice with deficient hepatic POR expression (Mutch et al, 2006(Mutch et al, , 2007, but neither study reported comparisons of the constitutive expression or activity of intestinal drugmetabolizing CYPs between wild-type and hepatic POR-null mice. The microarray data in the more recent study (Mutch et al, 2007) did show a modest increase in Fxr expression in the ileum of the hepatic POR-null mice, relative to that in WT mice, a finding confirmed here by RNA polymerase chain reaction analysis in the LCN mice.…”