major and important components are nutrients essential to humans , including vitamins , fatty acids , amino acids , carbohydrates and minerals . daily foods should contain all such essential nutrients and , additionally , sufficient calories to balance energy expenditure . hence , daily amounts of essential nutrients ( dietary reference intakes ) have been established in many countries including japan . the other components in the dietary foods are functional food factors ; they are not essential , but their daily consumption , in addition to satisfaction of the dietary reference intakes , is recognized to maintain homeostasis and exert several health benefits , for example , antioxidant , anti - inflammatory , anti - obesity , and anti - cancer actions . in the past few decades , many types of functional factors have been identified in dietary foods . however , their absorption rates are usually low , and many of these are difficult to be absorbed in the intact forms because of metabolization by biological processes before absorption . for example , flavonoid glycosides , which are widely distributed in the plant kingdom , are well known to be absorbed after some modifications . briefly , once consumed , flavonoid glycosides are usually hydrolyzed into the aglycone form by mucosal and bacterial enzymes in the digestive tract , and are subsequently metabolized into glucuronidated and sulfated derivatives via phase ii reactions . additionally , the absorption ratio of flavonoid glycosides is reported to be low ; around 1% of the consumption . to gain adequate beneficial effects , it is therefore mandatory to know whether functional food factors are absorbed in sufficient quantity , and then reach target organs while maintaining beneficial effects . these are the reason why the bioavailability of functional food factors has been well investigated using animal models . interestingly , recent studies have suggested that many of the biological processes in human displays an endogenous oscillation of about 24  h ( circadian rhythm ) , which is converted to accurate 24  h diurnal rhythms by resetting the clock genes with light exposure and/or food consumption at morning ( see the following section for further details ) . these biological processes include several parameters concerning in the absorption and metabolism of essential nutrients and drugs , and also the toxicity of environmental chemicals . hence , beneficial and toxicological effects of many essential nutrients , drugs and environmental chemicals are reported to be largely different according to consumption , administration and exposure time , respectively . transporter - mediated glucose uptake was greater at active phase compared with the inactive phase in rat duodenum . moreover , the frequencies of the micronucleated peripheral reticulocytes in the bone marrow from mice exposed to n - ethyl - n - nitrosourea at active phase were significantly higher than those in mice treated at inactive phase , indicating that genotoxic sensitivity to chemicals is different between active and inactive phases . this recent information shows the importance of knowing when to consume , administrate and expose target compounds , in addition to the amounts of these factors . however , many animal studies performed to evaluate the bioavailability of functional food factors have not taken into consideration the timing of consumption . in this review , we provide a perspective overview of the diurnal rhythm of biological processes involved in the bioavailability of functional food factors , particularly flavonoids . furthermore , the recent research topics involving several food factors that can affect circadian rhythm are focused . circadian rhythms are produced by a complex transcriptional - translational feedback loop , which revolves about a 24  h cycle . as shown in fig .  1 , the transcriptional regulators , circadian locomotor output cycles kaput ( clock ) and brain and muscle arnt - like protein 1 ( bmal1 ) , form a heterodimer . the clock / bmal1 heterodimer is a positive regulator , and activates expression of genes with e - box in the promoter regions . these are generally called  clock - controlled genes ( ccgs )  , and encode essential regulators of hormonal and metabolic pathway . period ( per ) mrna and cryptochrome ( cry ) the individual proteins , per and cry , make a complex ( per / cry ) that suppresses the transcription of its own genes by blocking the activity of clock / bmal1 heterodimer ( negative feedback ) . additionally , clock / bmal1 activates nuclear receptor subfamily 1 , group d , member 1 ( rev - erb ) and rar - related orphan receptor  ( ror ) , which regulate clock and bmal1 production via ror responsive elements ( rore ) in their promoters . this negative feedback loop revolves about a 24  h cycle , thereby resulting in free - run circadian rhythms , although these circadian rhythms are converted to accurate 24  h diurnal rhythms by resetting these clock genes with light exposure and/or food consumption at morning ( around active phase ) . the diurnal gene expression profiles consisted of the negative feedback loop ; clock , bmal1 , per1 , per2 , and cry1 on duodenum mucosa in mice were determined ( fig the samples were collected at 6  h intervals at 5 times from male c57bl/6 mice housed under a 12  h light/12  h dark cycle . these gene expressions suggested diurnal expression patterns ; maximum expressions of bmal1 and clock were located around the beginning of the light period , and per1 , per2 and cry were around the beginning of the dark period , as similar results have been reported by other research groups . mice and rats are nocturnal animals and , hence , their active and inactive phases are in the dark period and light period , respectively . the diurnal rhythms observed in the clock genes and ccgs expressions in human and rodents suggest similar patterns , although humans are usually diurnal , indicating biological rhythmicity is equiphase according to the active / inactive phases in both mammalian species . the diurnal gene expression profiles in mice duodenum mucosa related to xenobiotic transporter p - glycoprotein , multidrug resistance 1 ( mdr1 ) and regulation of absorption , main hexose transporters sodium - glucose co - transporter 1 ( sglt1 ) and glucose transporter 5 ( glut5 ) , and peptide transporter proton - coupled oligopeptide transporter 1 ( pept1 ) were further determined ( fig . expression of all genes exhibited diurnal rhythmicity with peak expression preceding the end of the light period , before nutrient arrival , similarly to major ccgs , per1 , per2 and cry1 . these diurnal rhythmicity of genes involved in the bioavailability of nutrients in the peripheral organs are reported to be shifted by restricted feeding in the light period , but weak effects on restricted feeding in the dark period , indicating that the ccgs in the peripheral organs might be reset accurately to a 24  h diurnal rhythm mainly by consumption of foods before the active phase , breakfast in case of humans . interestingly , hirao and colleagues reported that balanced diets containing carbohydrates / sugars and proteins are good for restricted feeding - induced entrainment of the peripheral circadian clock , but these effect was weak when consuming sugar alone . they also suggested that the standard diet , for example ain-93 m formula , might be the suitable balanced diet for entrainment on mice . rodents under ad libitum usually consume the diet on the beginning of dark period ( active phase ) . therefore , the studies considering the diurnal rhythmicity of biological processes might be able to be performed by using nocturnal rodents with standard balanced diets such as ain-93 m ad libitum , and these results will be possible to extrapolate the human events . table  1 summarizes the recent knowledge of diurnal profiles of major biological events , parameters in blood , liver and intestine , and hepatic and intestinal expression of genes involved in the bioavailability of functional food factors , particularly dietary flavonoids , in rodents . as described above , intestinal mrna expression , such as hexose transporters , peptide transporter , and xenobiotic transporter , exerts diurnal rhythms . additionally , the mrna levels involved in fat absorption ; microsomal triglyceride transfer protein ( mtp ) and apical sodium - dependent bile acid transporter ( asbt ) , also exert diurnal rhythms in a similar cycle . levels of intestinal proteins , such as sglt1 , pept1 , mtp and p - glycoprotein , and the enzymatic activities of maltase , sucrose and mtp transfer exert diurnal patterns , with the maximum reached around the beginning of the dark period . concomitantly , uptake levels of not only nutrients , such as glucose and dipeptide , but also drugs , such as the antibiotic ceftibuten and cardiac digoxin , are different depending on the administration period . glucose and peptide uptakes are basically higher at the dark period ( active phase ) than the light period ( inactive phase ) . additionally , diurnal variation in the intestinal accumulation of digoxin , a typical substrate of mdr1a , is reported by using mice intestinal ex vivo experiments . according to that study , the diurnal accumulation of digoxin in intestine is nearly anti - phase to the rhythmicity of p - glycoprotein expression and mdr1a gene expression . these results imply that the uptake and efflux of nutrients and drugs exert the administrating time - dependent differences , because the biological processes , such as sglt1 and mdr , have diurnal rhythmicity . although available data about the relations between the bioavailability of functional food factors and the timing of consumption have been limited yet , some studies suggest that the diurnal changes of biological process might be involved in the bioavailability . gastric emptying time is an important factor affecting the absorption of functional food factors . when bilberry anthocyanins , which are the major flavonoids mainly in berry fruits , were orally administered to c57bl/6 mice during the light or dark periods with same amounts , the gastric emptying time of anthocyanins was significantly faster upon administration at the dark period ( active phase ) than that of the light period ( inactive phase ) ( fig . as described above , many types of functional food factors , particularly flavonoids are absorbed after some modifications , such as hydrolysis and conjugation , but not in intact forms . gene expressions of many types of regulators involved in the metabolism of flavonoids follow a diurnal rhythm in rodents . as shown in table  1 , hepatic gene expression of sulfotransferases ( sult1a1 , sult1d1 ) and udp - glucuronosyltransferase ( ugt1a1 ) are maximal around the change to the dark period . the other pathways related to lipid and glucose metabolism also follow diurnal rhythms , including fatty acid synthase ( fasn ) , cytochrome p450 7a1 ( cyp7a1 ) and hmg - coa reductase ( hmgcr ) in the liver , and apolipoprotein ( apob and apoaiv ) and diglyceride acyltransferase ( dgat1 and dgat2 ) in the small intestine . these biological parameters are usually employed as the targets in order to evaluate the effects of functional food factors . interestingly , the endogenous antioxidant system , such as superoxide dismutase ( sod ) activity , is more active during the light period than the dark period in rodents . although all of mammals are homeothermic animals , body temperature has a diurnal rhythm ; around 1.5c higher during the middle of the dark period than during the middle of the light period in mice . oike and colleagues   reported that caffeine consumption ad libitum for a week lengthened the circadian locomotor rhythm in mice . retinoic acid was suggested to significantly upregulate per1 , per2 , and peroxisome proliferator - activated receptor  ( ppar ) expression in an e - box - dependent manner using mouse nih3t3 cells . another food factor , resveratrol , a grape polyphenol , was found to upregulate expression of bmal1 , per1 and per2 mrna in rat-1 fibroblast cells . these results suggest that several functional food factors affect the negative feedback loop shown in fig .  1 , and consequently might change the bioavailability of themselves and/or other food factors consumed together via controlling of diurnal biological processes in the peripheral organs . the ccgs in the peripheral organs are recognized to be reset accurately to a 24  h diurnal rhythm mainly by consumption of foods , which are balanced diet , but not single ingredient , before the active phase as described above . furthermore , feeding stimulus for 30  min significantly induces the expression of per2 and dec 1 within 1 h , and alter the transcript levels and circadian phases of other clock genes ( bmal1 , cry1 , per1 , and rev - erb ) in the liver at longer time intervals in rats . by contrast , effects of balanced diet and functional food factors on the circadian rhythmicity remains poorly understood at human . many biological processes involved in absorption and metabolism of functional food factors follow the diurnal rhythm . additionally , some functional food factors are suggested to affect directly the rhythms . hence , the evaluation of the bioavailability of functional food factors should take into consideration the timing of consumption .
in the past few decades , many types of functional factors have been identified in dietary foods ; for example , flavonoids are major groups widely distributed in the plant kingdom . 
 however , the absorption rates of the functional food factors are usually low , and many of these are difficult to be absorbed in the intact forms because of metabolization by biological processes during absorption . to gain adequate beneficial effects , it is therefore mandatory to know whether functional food factors are absorbed in sufficient quantity , and then reach target organs while maintaining beneficial effects . 
 these are the reasons why the bioavailability of functional food factors has been well investigated using rodent models . 
 recently , many of the biological processes have been reported to follow diurnal rhythms recurring every 24  h. therefore , absorption and metabolism of functional food factors influenced by the biological processes may vary with time of day . 
 consequently , the evaluation of the bioavailability of functional food factors using rodent models should take into consideration the timing of consumption . in this review , 
 we provide a perspective overview of the diurnal rhythm of biological processes involved in the bioavailability of functional food factors , particularly flavonoids .