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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.