臺灣博碩士論文加值系統

輔仁大學營養科學系碩士論文摘要
研究所別：營養科學系碩士班 研究生：陳琦仁
論文名稱：以右旋半乳糖注射大鼠模式探討維生素B2缺乏對腎臟解毒酵素之影響
指導教授：駱菲莉 博士

本研究利用皮下注射每公斤體重100毫克右旋半乳糖 (DG) 誘發大鼠老化模式探討維生素B2缺乏對老化個體腎臟解毒系統之影響。將3週齡大鼠分成控制組 (B2充足飲食+皮下注射phosphate buffer saline, N)、誘發老化組 (B2充足飲食+皮下注射DG, A)、老化缺乏組 (B2缺乏飲食+皮下注射DG, D) 與老化配對餵食組(與老化缺乏組攝食量配對且維生素B2充足飲食+皮下注射DG, P) 等4組，持續13週。犧牲前一天餵食各組半數動物每公斤體重20毫克之3-Methylcholanthrene (3-MC)，誘發其腎臟解毒系統。結果顯示老化缺乏組之紅血球穀胱甘肽還原酶係數自第二週起顯著提高，確認動物呈現維生素B2缺乏，並顯著降低其活動力、攝食量、食物利用率、體重與腎臟flavin containing monooxygenase (FMO) 活性，增加腎臟重量百分比；血紅素、血中尿素氮、細胞色素P450 (CYP)、穀胱苷肽硫轉移酶、榖胱甘肽還原酶、UDP-glucurono-syltransferase、NAD(P)H : quinine oxidoreductase 1 (NQO1) 與它組無顯著差異。急性3-MC投予後，老化缺乏組CYP 1A2、2B1活性顯著高於誘發老化組；NQO1活性與蛋白質表現量顯著低於誘發老化組，其餘酵素活性與它組無顯著差異。急性3-MC投予下，老化缺乏組FMO活性顯著下降。比較長期皮下注射DG之影響，誘發老化組與控制組其解毒酵素活性皆無顯著差異，急性3-MC投予後，誘發老化組CYP 1A1、2B1、3A4顯著低於控制組。綜合上述，急性3-MC投予後，長期皮下注射DG顯著降低腎臟CYP活性；維生素B2缺乏可能造成腎臟一、二期解毒酵素活性比例改變。

關鍵字：維生素B2、右旋半乳糖、3-methylcholanthrene、腎臟解毒酵素

The effect of riboflavin deficiency on renal detoxification system of D-galactose injected rats

Chi Ren Chen

The purpose of the study was to employ a D-galactose (DG) induced aging model to evaluate the influence of riboflavin status on renal detoxification system. The weaning Sprague-Dawely rats were randomly divided into four groups: control (riboflavin sufficient + saline, N); DG induced aging (riboflavin sufficient + DG, A); riboflavin deficient (riboflavin deficient + DG, D); paired feeding (paired feeding with D + DG, P). Twenty-four hours before being sacrificed, half number of the animals from each group were fed 20 mg/kg body weight of 3-MC to induce their renal detoxification system. The results showed a significant increase EGRAC in D group since the 2nd week indicating successful induction of riboflavin deficiency. The activity, intake, feed efficiency, weight, and renal favin containing monooxygenase activites were significantly lower in D group than in other groups. But the relative kidney weight were significantly higher in D group than other groups. The hemoglobin and blood urea nitrogen level, Cytochrome P450 (CYP), glutathione S transferase, glutathione reductase, UDP-Glucurono-syltransferase, NAD(P)H : quinine oxidoreductase 1 (NQO1) activiies were not significantly changed. After acute 3-MC administration, CYP 1A2, 2B1 activies were significantly higher in D group than in A group. NQO1 activies and protein expression were significantly lower in D group than in A group. The detoxification enzyme activies showed no significant difference between N and A groups. After acute 3-MC administration, CYP 1A1, 2B1, 3A4 activies were significantly lower in A group than in N groups. In summary, under acute 3-MC administration, DG injection significantly decreased renal CYP activies. On other hand, riboflavin deficiency may result in changes in the proportion of renal detoxification Phase Ⅰ enzyme activies to Phase Ⅱ enzyme activies.

Key: riboflavin, D-galactose, 3-methylcholanthrene, renal detoxificantion enzymes

目錄
中文摘要………………………………………………………………………………Ⅰ
英文摘要………………………………………………………………………………Ⅱ
目錄……………………………………………………………………………………Ⅲ
表目錄…………………………………………………………………………………Ⅸ
圖目錄…………………………………………………………………………………Ⅹ
縮寫表………………………………………………………………………………ⅩⅡ
第一章 前言…………………………………………………………………………1
第二章 文獻回顧……………………………………………………………………2
一、解毒系統簡介………………………………………………………………………2
(一) 腎臟解毒系統……………………………………………………………2
(二) 細胞色素P450 (cytochrome P450) ………………………………………4
(1) 細胞色素2家族 (Cytochrome 1 family) ……………………………5
(2) 細胞色素2家族 (Cytochrome 2 family) ……………………………5
(3) 細胞色素3家族 (Cytochrome 3 family) ……………………………6
(4) 細胞色素P450還原. (Cytochrome P450 reductase) ………………6
(三) flavin containing monooxygenase…………………………………………6
(四) NAD(P)H : quinine oxidoreductase………………………………………8
(五) 穀胱..硫轉移. (glutathione S traansferase, GST) …………………9
(六) UDP-glucuronosyltransferase………………………………………………9
(七) 3-甲基瞻蔥 (3-methylcholanthrene)簡介………………………………10
二、維生素B2簡介………………………………………………………………11
(一) 維生素B2之理化性質與食物來源………………………………………11
(二) 維生素B2之代謝…………………………………………………………11
IV
(1) 維生素B2之吸收……………………………………………………11
(2) 維生素B2之運輸與儲存……………………………………………12
(3) 維生素B2之排泄……………………………………………………12
(三) 維生素B2之人體需求量…………………………………………………13
(四) 維生素B2之生化功能……………………………………………………14
(1) 維生素B2與抗氧化…………………………………………………15
(2) 維生素B2與腸道發育………………………………………………15
(3) 維生素B2與神經系統………………………………………………16
(4) 維生素B2與心血管疾病……………………………………………16
(五) 維生素B2缺乏之臨床症狀………………………………………………17
(六) 維生素B2營養狀態評估指標……………………………………………17
(1) 尿液排除量…………………………………………………………17
(2) 紅血球榖胱甘.還原.活性係數…………………………………17
(七) 維生素B2缺乏與解毒系統………………………………………………18
三、老化……………………………………………………………………………19
(一) 簡介老化假說……………………………………………………………19
(二) 老化對腎臟解毒系統之影響……………………………………………20
(三) 右旋半乳糖誘發老化模式………………………………………………21
四、研究目的與假說………………………………………………………………22
第三章 材料與方法………………………………………………………………23
一、實驗設計……………………………………………………………………23
二、動物飼養環境………………………………………………………………24
三、飼料配置……………………………………………………………………24
(一) 飼料成分及配方…………………………………………………………24
(二) 飼料製備程序……………………………………………………………26
V
四、樣本收集與處理……………………………………………………………26
(一) 血液………………………………………………………………………26
(二) 腎臟………………………………………………………………………27
(三) 腎臟微粒體………………………………………………………………27
五、分析項目與方法……………………………………………………………27
(一) 紅血球穀胱甘.還原.活性係數………………………………………27
(二) 血中尿素氮含量測定……………………………………………………28
(三) 血紅素測定………………………………………………………………28
(四) 腎臟穀胱甘.還原.活性 (GR) 活性…………………………………28
(五) 腎臟 cytochrome 1A1活性 (Ethroxyresorufin O-deethylase , EROD) …28
(六) 腎臟 cytochrome 1A2活性 (Methoxyresorufin O-demethylase, MROD) 29
(七) 腎臟 cytochrome 2B1活性 (Pentoxyresorufin O-depentylase, PROD) …29
(八) 腎臟 cytochrome 3A4活性 (CYP 3A4)…………………………………29
(九) 腎臟 flavin-containing monooxygenase (FMO) 活性……………………30
(十) 腎臟榖胱甘.硫轉移. (GST) 活性……………………………………30
(十一) 腎臟 NAD(P)H: quinone oxidoreductase 1 (NQO1) 活性……………30
(十二) 腎臟 NAD(P)H: quinone oxidoreductase 1 (NQO1) 西方點墨法. …31
(十三) 腎臟 UDP-glucuronosyltransferase (UGT) 活性……………………31
(十四) 蛋白質含量測定………………………………………………………31
六、 統計分析……………………………………………………………………31
第四章 結果………………………………………………………………………32
一、 動物生長情形………………………………………………………………33
(一) 動物外觀…………………………………………………………………33
(二) 動物攝食量、食物利用率、體重與腎臟重量百分比與之變化…………33
二、 動物維生素B2營養狀態與血紅素…………………………………………36
VI
(一) 維生素B2營養狀態與長期皮下注射DG對動物紅血球穀胱甘.還原.
活性係數的影響…………………………………………………………36
(二) 維生素B2營養狀態與長期皮下注射DG對動物血紅素的影響………37
三、 維生素B2營養狀態與長期皮下注射DG對動物血中尿素氮的影響……37
四、 維生素B2營養狀態與長期皮下注射DG對動物腎臟第一期酵素活性的影響…………………………………………………………………………38
(一) Cytochrome 1A1活性 (Ethroxyresorufin O-deethylase , EROD) ………38
(二) Cytochrome 1A2活性 (Methoxyresorufin O-demethylase, MROD) ……38
(三) Cytochrome 2B1活性 (Pentoxyresorufin O-depentylase, PROD) ………39
(四) Cytochrome 3A4 (CYP 3A4) 活性………………………………………40
(五) Flavin-containing monooxygenase (FMO) 活性…………………………40
五、 維生素B2營養狀態與長期皮下注射DG對動物腎臟第二期酵素活性的影響……………………………………………………………………………41
(一) 榖胱甘.還原. (GR) 活性……………………………………………41
(二) 榖胱甘.硫轉移. (GST) 活性………………………………………42
(三) UDP-glucuronosyltransferase (UGT) 活性………………………………42
(四) NAD(P)H: quinone oxidoreductase 1 (NQO1) 活性……………………43
(五) NAD(P)H: quinone oxidoreductase 1 (NQO1) 蛋白質表現量…………44
第五章 討論………………………………………………………………………46
一、 維生素B2營養狀態對動物生長參數之影響………………………………46
(一) 動物外觀與活動力………………………………………………………46
(二) 動物攝食量、食物利用率、體重與腎臟重量百分比……………………46
二、 維生素B2營養狀態對紅血球穀胱甘.還原.活性係數、血紅素與血中尿素氮之影響…………………………………………………………………47
(一) 紅血球穀胱甘.還原.活性係數………………………………………47
VII
(二) 血紅素……………………………………………………………………48
(三) 血中尿素氮………………………………………………………………49
三、右旋半乳糖注射對動物生長參數之影響…………………………………49
(一) 動物外觀與活動力………………………………………………………49
(二) 體重………………………………………………………………………50
四、維生素B2營養狀態對動物腎臟第一期酵素活性的影響………………50
(一) CYP………………………………………………………………………50
(二) FMO………………………………………………………………………51
五、維生素B2營養狀態對動物腎臟第二期酵素活性的影響…………………52
(一) 榖胱甘.還原. (GR) …………………………………………………52
(二) 榖胱甘.硫轉移. (GST) 與UGT……………………………………52
(三) NQO1……………………………………………………………………53
六、右旋半乳糖注射對動物腎臟解毒酵素活性的影響………………………55
七、急性3-MC投予對動物腎臟解毒酵素活性的影響…………………………56
第六章 結論………………………………………………………………………58
第七章 參考文獻…………………………………………………………………77
附錄一、紅血球榖胱甘.還原.活性係數 (EGRAC) 之測定……………………92
附錄二、血紅素 (HB) 之測定………………………………………………………95
附錄三、血中尿素氮 (BUN) 之測定…………………………………………………96
附錄四、Cytochrome 1A1活性之測定……………………………………………… 98
附錄五、Cytochrome 1A2活性之測定………………………………………………100
附錄六、Cytochrome 2B1活性之測定………………………………………………102
附錄七、腎臟 Cytochrome 3A4活性之測定………………………………………104
附錄八、腎臟Flavin-containing monooxygenase (FMO) 活性之測定……………106
附錄九、腎臟穀胱甘.還原. (GR) 活性之測定…………………………………108
VIII
附錄十、腎臟穀胱甘.硫轉移. (GST) 活性之測定……………………………110
附錄十一、腎臟UDP-glucuronosyltransferase (UGT) 活性之測定………………112
附錄十二、腎臟 NAD(P)H: quinone oxidoreductase 1 (NQO1) 活性之測定……114
附錄十四、NAD(P)H:Quinone Oxidoreductase 1西方點墨法 ( Western blot) 測定方
法………………………………………………………………………116
附錄十五、蛋白質定量之測定方法…………………………………………………123

參考文獻

劉宗榮、康照洲、郭明良、翁祖輝。基礎毒理學。台北市：藝軒圖書出版社，2003:33-35。

行政院衛生署。國人膳食營養素參考攝取量及其說明。台北市：行政院衛生署，2003:126-41。

施懿庭 (2009) 慢性維生素B2缺乏過程對大白鼠維生素B2營養生化指標與肝臟基因表現之影響。天主教輔仁大學營養科學研究所碩士論文。

魏鏇珮 (2010) 維生素B2營養狀況對於右旋半乳糖注射大暑肝臟抗氧化系統之影響。天主教輔仁大學營養科學研究所碩士論文。

Adelekan DA, Thurnham DI. Effects of combined riboflavin and iron deficiency on the hematological status and tissue iron concentrations of the rat. J Nutr. 1986;116:1257-65.

Ahmed F, Bamji MS. Biochemical basis for the "riboflavin defect" associated with the use of oral contraceptives. A study in female rats. Contraception. 1976;14:297-307.

Anders MW. Metabolism of drugs by the kidney. Kidney Int.1980; 18:636–47.

Anders MW, Dekant W. Aminocylases. Adv Pharmacol. 1994;27:431–44.

Asaoka Y, Sakai H, Hirata A, Sasaki J, Goryo M, Miyamoto Y, Yanai T, Masegi T, Okada K. Detection of initiation activity of 1,2-dimethylhydrazine in in vivo medium-term liver initiation assay system using 4-week-old rats without hepatocellular proliferative stimuli during the test chemical treatment period. J Vet Med Sci. 2010;72:43-53.

Bates C. Riboflavin. Int J Vitam Nutr Res. 1993;63:274-7.

Bamji MS, Sharda D. Hepatic enzymes and vitamin deficiency. Biochem J. 1972;128:58.

Benson AN, Hunckler MJ, Talalay P. Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity. PNAS. 1980;77:5216–20.

Betz A, Ren XD, Ennis SR, Hultquist DE. Riboflavin reduces edema in focal cerebral ischemia. Acta Neurochir Suppl (Wien). 1994;60:314–7.

Bianchet MA, Faig M, Amzel LM. Structure and mechanism of NAD[P]H:quinone acceptor oxidoreductases (NQO). Methods Enzymol. 2004;382:144-74.

Bock KW, Burchell B, Dutton GJ, Hanninen O, Mulder GJ, Own IS, Siest G and Tephly TR. UDP-glucuronosyltransferase activities. Guidelines for consistent interim terminology and assay conditions. Biochem Pharmacol.1983;32:953-5.

Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995;274:1049–57.

Bowes RC III, Parish AR, Steinberg MA, Willet KL, Zhao W, Savas U, Jefcoate CR, Safe SH, Ramos KS. atypical cytochrome P450 induction profiles in glomerular mesangial cells at the mRNA and enzyme level Evidence for CYP 1A1 and CYP 1B1 expression and their involvement in benzo[A]pyrene metabolism. Biochem Pharmacol. 1996;52:587-95.

Brady PS, Brady LJ, Parsons MJ, Ullrey DE, Miller ER. Effects of riboflavin deficiency on growth and glutathione peroxidase system enzymes in the baby pig. J Nutr. 1979;109:1615-22.

Bro-Ramussen F. the riboflavin requirements of animals and men and associated metabolic relations. 1. Technique of estimating requirement, and modifying circumstances. Nutr Abstr Rev. 1985;28:1-23.

Butler BF, Topham RW. Comparison of changes in the uptake and mucosal processing of iron in riboflavin-deficient rats. Biochem Mol Biol Int. 1993;30:53-61.

Cappiello M, Giuliani L, Pacifici GM. Distribution of UDP-glucuronosyltransferase and its endogenous substrate uridine 59-diphosphoglucuronic acid in human tissues. Eur J Clin Pharmacol. 1991;41:345–50.

Cashman JR. In vitro metabolism: FMO and related oxygenations. 1st. ed. In: Wolfe TF, ed. Handbook of Drug Metabolism. Marcel Dekker Inc: Ann Arbor, 1999:477-506.

Cashman JR, Camp K, Fakharzadeh SS, Fennessey PV, Hines RN, Mamer OA, Mitchell SC, Nguyen GP, Schlenk D, Smith RL, Tjoa SS, Williams DE, Yannicelli S. Biochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FMO3) related to trimethylaminuria. Curr Drug Metab. 2003;4:151-70.

Cavalieri E, Chakravarti D, Guttenplan J, Hart E, Ingle J, Jankowiak R, Muti P, Rogan E, Russo J, Santen R, Sutter T. Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention. Biochim Biophys Acta. 2006;1766:63-78.

Celius T, Pansoy A, Matthews J, Okey AB, Henderson MC, Krueger SK, Williams DE. Flavin-containing monooxygenase-3: induction by 3-methylcholanthrene and complex regulation by xenobiotic chemicals in hepatoma cells and mouse liver. Toxicol Appl Pharmacol. 2010;247:60-9.

Cojocel C, Maita K, Pasino DA, Kuo C, Hook JE. Metabolic heterogeneity of the proximal and distal kidney tubules. Life Sci. 1983;33:855–61.

Cooperman JM, Lopez R. Riboflavin. 2nd. ed. In: Machlin LJ, ed. Handbook of vitamins. Marcel Dekker Inc: New York, 1991:283-309.

Cressey G, Roberts DR, Snowden CP. Renal tubular injury after infrarenal aortic aneurysm repair. J Cardiothorac Vasc Anesth. 2002;16:290-3.

Cui X, Wang L, Zuo P, Han Z, Fang Z, Li W, Liu J. D-galactose-caused life shortening in Drosophila melanogaster and Musca domestica is associated with oxidative stress. Biogerontology 2004;5:317-25. J Neurosci Res. 2006;83:1584-90.

Cui X, Zuo P, Zhang Q, Li X, Hu Y, Long J, Packer L, Liu J. Chronic systemic D-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: protective effects of R-alpha-lipoic acid. J Neurosci Res. 2006;83:1584-90.

Danson S, Ward TH, Butler J, Ranson M. DT-diaphorase: a target for new anticancer drugs. Cancer Treat Rev. 2004;30:437-49.

de Lannoy IA, Hirayama H, Pang KS. A physiological model for renal drug metabolism: Enalapril esterolysis to elalaprilat in the isolated perfused rat kidney. J Pharmacokinet Biopharm. 1990;18:561–87.

Deng HB, Cui DP, Jiang JM, Feng YC, Cai NS, Li DD. Inhibiting effects of Achyranthes bidentata polysaccharide and Lycium barbarum polysaccharide on nonenzyme glycation in D-galactose induced mouse aging model. Biomed Environ Sci. 2003;16:267-75.

de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet. 1999 ;37:485-505.

Durnas C, Loi CM, Cusack BJ. Hepatic drug metabolism and aging. Clin Pharmacokinet. 1990;19:359-89.

Dutta P, Gee M, Rivlin RS, Pinto J. Riboflavin deficiency and glutathione metabolism in rats: possible mechanisms underlying altered responses to hemolytic stimuli. J Nutr. 1988;118:1149-57.
Dutta P, Seirafi J, Halpin D, Pinto J, Rivlin R. Acute ethanol exposure alters hepatic glutathione metabolism in riboflavin deficiency. Alcohol. 1995;12:43-7.

Edwards YH, Potter J, Hopkinson DA. Human FAD-dependent NAD(P)H diaphorase. Biochem J. 1980;187:429–36.

Elfarra AA, Hwang IY. Targeting of 6-mercaptopurine to the kidneys: Metabolism and kidney-selectivity of S-(6-purinyl)-L-cysteine analogs in rats. Drug Metab Dispos. 1993;21:841–5.

Endou H. Distribution and some characteristics of cytochrome P-450 in the kidney. J Toxicol Sci. 1983;8:165–76.

Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 1999;286:487– 91.

Glatzle D, Weber F, Wiss O. Enzymatic test for the detection of a riboflavin deficiency. NADPH-dependent glutathione reductase of red blood cells and its activation by FAD in vitro. Experientia 1968;24:1122.

Gibson JB. Gonadal function in galactosemics and in galactose-intoxicated animals. Eur J Pediatr. 1995;154:S14–S20.

Green T, Odum J. Structure/activity studies of the nephrotoxic and mutagenic action of cysteine conjugates of chloro- and fluoroalkenes. Chem Biol Interact. 1985;54:15-31.

Gyorgy P. Riboflavin. In: Gerald F, Combs, JR, eds. The vitamins- fundamental aspects in nutrition and health. San Diego: Academic Press, 1992:271-87.

Habig WH and Jakoby WB. Assays for differentiation of glutathione S-transferases. Methods Enzymol. 1981;77:398-405.

Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11:298-300.

Henderson CJ, Wolf CR. Evidence that the androgen receptor mediates sexual differentiation of mouse renal cytochrome P450 expression. Biochem J. 1991;278 :499-503.

Hernandez D, Janmohamed A, Chandan P, Phillips IR, Shephard EA. Organization and evolution of the flavincontaining monooxygenase genes of human and mouse: identification of novel gene and pseudogene clusters. Pharmacogenetics. 2004;14:117–30.

Hiley C, Bell J, Hume R, Strange R. Differential expression of alpha and pi isoenzymes of glutathione S-transferase in developing human kidney. Biochim Biophys Acta. 1989;990:321-4.

Hines RN. Developmental and tissue-specific expression of human flavincontaining monooxygenases 1 and 3. Expert Opin Drug Metab Toxicol. 2006 Feb;2:41-9.

Hines RN, Hopp KA, Franco J, Saeian K, Begun FP. Alternative processing of the human FMO6 gene renders transcripts incapable of encoding a functional flavin-containing monooxygenase. Mol Pharmacol. 2002;62:320-5.

Hjelle JT, Peterson DR, Hjelle JJ. Drug metabolism in isolated proximal tubule cells. J Pharmacol Exp Ther. 1983;224:699–705.

Horwitt MK, Harvey CC, Hills OW, Liebert E. Correlation of urinary excretion of riboflavin with dietary intake and symptoms of ariboflavinosis. J Nutr. 1950;41:247-64.

Ho SC, Liu JH, Wu RY. Establishment of the mimetic aging effect in mice caused by D-galactose. Biogerontology. 2003;4:15-8.

Hosten AO. SourceClinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. In: Walker HK, Hall WD, Hurst JW, ed. Boston: Butterworths. 1990:874-8.

Huang J, Tian L, Wu X, Yang H, Liu Y. Effects of dietary riboflavin levels on antioxidant defense of the juvenile grouper Epinephelus coioides. Fish Physiol Biochem. 2010:55-62.

Hultquist DE, Xu F, Quandt KS, Shlafer M, Mack CP. Evidence that NADPH-dependent methaemoglobin reductase and administered riboflavin protect tissue from oxidative injury. Am J Hematol 1993;42:13–8.

Hustad S, Ueland PM, Vollset SE, Zhang Y, Bjorke-Monsen AL, Schneede J. Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism. Clin Chem 2000;46:1065–71.

Innis WS, McCormick DB, Merrill AH Jr. Variations in riboflavin binding by human plasma: identification of immunoglobulins as the major proteins responsible. Biochem Med. 1986;34:151–65.

Johnson WD, Storts RW. Peripheral neuropathy associated with dietary riboflavin deficiency in the chicken. I. Light microscope study. Vet Pathol 1988;25:9–16.

Jortner BS, Cherry J, Lidsky TI, Manetto C, Shell L. Peripheral neuropathy of dietary riboflavin deficiency in chickens. J Neuropath Exp Neurol 1987;46:544–55.

Jucker M, Ingram DK. Murine models of brain aging and age-related neurodegenerative diseases. Behav Brain Res. 1997;85:1-26.

Kim H, Reddy S, Novak RF. 3-Methylcholanthrene and pyridine effects on CYP 1A1 and CYP 1A2 expression in rat renal tissue. Drug Metab Dispos. 1995;23:818-24.

Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev. 2009;41:67-76.
Krajka-Kuźniak V, Szaefer H, Baer-Dubowska W. Modulation of 3-methylcholanthrene-induced rat hepatic and renal cytochrome P450 and phase II enzymes by plant phenols: protocatechuic and tannic acids. Toxicol Lett. 2004;152:117-26.

Krishna DR, Klotz R. Extrahepatic metabolism of drugs in humans. Clin Pharmacokinet. 1994;26:144–60.

Kohle C, Bock KW. Coordinate regulation of phase I and IIxenobiotic metabolisms by the Ah receptor and Nrf2. Biochem. Pharmacol.2007;73:1853–62.

Koukouritaki SB, Simpson P, Yeung CK, Rettie AE, Hines RN. Human hepatic flavin-containing monooxygenases 1 (FMO1) and 3 (FMO3) developmental expression. Pediatr Res. 2002;51:236-43.

Kumar A, Dogra S, Prakash A. Effect of carvedilol on behavioral, mitochondrial dysfunction, and oxidative damage against D-galactose induced senescence in mice. Naunyn Schmiedebergs Arch Pharmacol. 2009;380:431-41.

Lakshmi R, Lakshmi AV, Bamji MS. Mechanisms of impaired skin collagen maturity in riboflavin or pyridoxine deficiency. J Biosci 1990;15:289–95.

Lans M, Alfrey CP, Mengel CE, Doherty MA, Doherty J. The rapid induction of Human riboflavin deficiency with galactoflavin. J Clin Invest. 1964;43:357-73.

Lan Q, Zhang L, Li G, Vermeulen R, Weinberg RS, Dosemeci M, Rappaport SM, Shen M, Alter BP, Wu Y, Kopp W, Waidyanatha S, Rabkin C, Guo W, Chanock S, Hayes RB, Linet M, Kim S, Yin S, Rothman N, Smith MT. Hematotoxicity in workers exposed to low levels of benzene. Science. 2004;306:1774-6.

LeBlanc JG, Burgess C, Sesma F, de Giori GS, van Sinderen D. Lactococcus lactis is capable of improving the riboflavin status in deficient rats. Br J Nutr.2005;94:262-7.

Le Couteur DG, McLean AJ. The aging liver. Drug clearance and an oxygen diffusion barrier hypothesis. Clin Pharmacokinet. 1998;34:359-73.

Lee C, Hutson JR, Tzau VK, Riddick DS. Regulation of constitutive mouse hepatic cytochromes P450 and growth hormone signaling components by 3-methylcholanthrene. Drug Metab Dispos. 2006;34:1530-8.

Leshner RT. Riboflavin deficiency—a reversible neurodegenerative disease. Ann Neurol 1981;10:294–5.

Lin JH, Wong BK. Complexities of glucuronidation affecting in vitro-in vivo extrapolation. Curr Drug Metab. 2002;3,:623–46.

Li, WB, Wei F, Fan M, Zhang JL, Zhang BL, Ma XC, Yang WP, Wei W. Mimetic brain aging effect induced by D-galactose in mice. Chinese J Pharm Toxicol. 1995;9:93–5.

Litterst CL, Mimnaugh EG, Reagan RL, Gram TE. Comparison of in vitro drug metabolism by lung, liver and kidney of several common laboratory species. Drug Metab Dispos. 1975:3:259–65.

Lohr JW, Willsky GR, Acara MA. Renal drug metabolism. Pharmacol Rev. 1998;50:107-41.

Lock EA, Reed CJ. Xenobiotic metabolizing enzymes of the kidney. Toxicol Pathol. 1998;26:18-25.

Mackenzie PI, Gregory PA., Gardner-Stephen DA, Lewinsky RH, Jorgensen BR, Nishiyama T. Regulation of UDP glucuronosyltransferase genes. Curr Drug Metab. 2003;4:249– 57.

Manore MM. Effect of physical activity on thiamine, riboflavin, and vitamin B-6 requirements. Am J Clin Nutr. 2000;72:598S-606S.

McCormick DB, Greene HL. vitamins. In: Burtis CA, Ashwood ER, eds. Tietz textbook of clinical chemistry. Philadelphia: Saunders,1994.

McCormick DB, Innis WSA, Merrill AH Jr, Bowers-Komro DM, Oka M, Chastain JL. An update on flavin metabolism in rats and humans. In: Edmondson DE, McCormick DB, eds. Flavin and flavoproteins. New York: Walter de Gruyter, 1988:459–71.

Medvedev ZA. An attempt at a rational classification of theories of ageing. Biol Rev Camb Philos Soc. 1990;65:375-98.

Mitchell SC and Smith RL. Trimethylaminuria: the fish malodor syndrome. Drug Metab Dispos. 2001;29:517-21.

Mohandas J, Marshall JJ, Duggin GG, Horvath JS, Tiller DJ. Differential distribution of glutathione and glutathione-related enzymes in rabbit kidney. Possible implications in analgesic nephropathy. Biochem Pharmacol. 1984;33:1801-7.

Montano MM, Chaplin LJ, Deng H, Mesia-Vela S, Gaikwad N, Zahid M, Rogan E. Protective roles of quinone reductase and tamoxifen against estrogen-induced mammary tumorigenesis. Oncogene. 2007;26(24):3587-90.

Muhlberg W, Platt D. Age-dependent changes of the kidneys: pharmacological implications. Gerontology. 1999;45:243–253.

Murray GI, Barnes TS, Sewell HF, Ewen SW, Melvin WT, Burke MD. The immunocytochemical localisation and distribution of cytochrome P-450 in normal human hepatic and extrahepatic tissues with a monoclonal antibody to human cytochrome P-450. Br J Clin Pharmacol. 1988;25:465-75.

Nichoalds GE. Assessment of status riboflavin nutriture by assay of erythrocyte glutathione reductase activity. Clin Chem. 1974;20:624-8.

Orr WC, Sohal R. Extension of life-span by overexpression of superoxide and catalase in Drosophila melanogaster. Science. 1994;263:1128-30.

Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Norton WN, Daskal I, Savage H, Seibert R, Busch H, Lane M. Effects of riboflavin deficiency on the ultrastructure of rat sciatic nerve fibres.Am J Pathol 1976;85:651–60.

Overby LH, Carver GC, Philpot RM. Quantitation and kinetic properties of hepatic microsomal and recombinant flavin-containing monooxygenases 3 and 5 from humans. Chem Biol Interact. 1997;106:29-45.

Padmaja PA, Lakshmi AM, Bamji MS. Interpretation of erythrocyte glutathione reductase activation test values for assessing riboflavin status. Eur J Clin Nutr. 1992;46:753-8.

Patel JM, Pawar SS. Riboflavin and drug metabolism in adult male and female rats. Biochem Pharmacol. 1974;23:1467-77.

Phillips IR, Dolphin CT, Clair P, Hadley MR, Hutt AJ, McCombie RR, Smith RL, Shephard EA. The molecular biology of the flavincontaining monooxygenases of man. Chem Biol Interact. 1995;96:17–32.

PhillipS IR, Shephard EA. Flavin-containing monooxygenases: mutations, disease and drug response. Trends Pharmacol Sci. 2008;29:294-31.

Powers HJ. Experiment to determine the effect of riboflavin deficiency at weaning on iron economy and heme synthesis. Ann Nutr Metab. 1985;29:261-6.

Powers HJ, Weaver LT, Austin S, Beresford JK. A proposed intestinal mechanism for the effect of riboflavin deficiency on iron loss in the rat. Br J Nutr. 1993;69:553-61.

Prentice AM, Bates CJ. A biochemical evaluation of the erythrocyte glutathione reductase (EC 1.6.4.2) test for riboflavin status. 1. Rate and specificity of response in acute deficiency. Br J Nutr 1981;45:37–52.

Reddi AS. Riboflavin nutritional status and flavoprotein enzymes in normal and genetically diabetic KK mice. Metabolism. 1978;27:531-7.

Reddi AS. Riboflavin nutritional status and flavoprotein enzymes in streptozotocin-diabetic rats. Biochim Biophys Acta. 1986;882:71-6.

Ren Y, Yang X, Niu X, Liu S, Ren G. Chemical characterization of the avenanthramide-rich extract from oat and its effect on D-galactose-induced oxidative stress in mice. J Agric Food Chem. 2011;59:206-11.

Ritter JK. Roles of glucuronidation and UDP-glucuronosyltransferases in xenobiotic bioactivation reactions. Chem Biol Interact. 2000;129:171–193.

Rozell B, Hansson HA, Guthanberg C, Tahir MK, Mannervik B. Glutathione transferases of classes alpha, mu and pi show selective expression in different regions of rat kidney. Xenobiotica. 1993;23:835-49.

Rush GF, Hook JB. Characteristics of renal UDP-glucuronyltransferase. Life Sci. 1984;35:145–53.

Schlager JJ, Powis G. Cytosolic NAD(P)H:(quinone-acceptor) oxidoreductase in human and normal tissue: effects of cigarette smoking and alcohol. Int J Cancer. 1990;45:403–9.

Siegel D, Gibson NW, Preusch PC, Ross D. Metabolism of mitomycin C by DT-diaphorase: role in mitomycin C-induced DNA damage and cytotoxicity in human colon carcinoma cells. Cancer Res. 1990;50:7483–7489.

Shargel L, Mazel P. Effect of riboflavin deficiency on phenobarbital and 3-methylcholanthrene induction of microsomal drug-metabolizing enzymes of the rat. Biochem Pharmacol. 1973;22:2365-73.

Song X, Bao M, Li D, Li YM. Advanced glycation in D-galactose induced mouse aging model. Mech Ageing Dev. 1999;108:239-51.

Sreerama L, Hedge MW, Sladek NE. Identification of a class 3 aldehyde dehydrogenase in human saliva and increased levels of this enzyme, glutathione S-transferases, and DT-diaphorase in the saliva of subjects who continually ingest large quantities of coffee or broccoli. Clin Cancer Res. 1995:1:1153–63.

Stadtman ER. Protein oxidation and aging. Science. 1992:257:1220-4.

Steier M, Lopez R, Cooperman JM. Riboflavin deficiency in infants and children with heart disease. Am Heart J. 1976;92:139-43.

Taniguchi M. Effects of riboflavin deficiency on lipid peroxidation of rat liver microsomes. J Nutr Sci Vitaminol (Tokyo). 1980;26:401-13.

Tian JZ, Song CX, Ren Y, Liu XH, Yuan ZX. Effects of Da Huang formula on D-galactose induced aging mice model. Chinese J Gerontol. 1996;16: 39–40.

Tillotson JA, Sauberlich HE. Effect of riboflavin depletion and repletion on the erythrocyte glutathione reductase in the rat. J Nutr. 1971;101:1459-66.

Treacy EP, Akerman BR, Chow LM, Youil R, Bibeau C, Lin J, Bruce AG, Knight M, Danks DM, Cashman JR, Forrest SM. Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Hum Mol Genet. 1998;7:839-45.

Tukey RH, Strassburg CP. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol. 2000;405:81– 616.

van Muiswinkel FL, de Vos RA, Bol JG, Andringa G, Jansen Steur EN, Ross D, Siegel D, Drukarch B. Expression of NAD(P)H:quinone oxidoreductase in the normal and Parkinsonian substantia nigra. Neurobiol Aging. 2004;25:1253-62.

Vina J, Borras C, Miquel J. Theories of aging. IUBMB life. 2007;59:249-54.

Vaidya VS, Ozer JS, Dieterle F, Collings FB, Ramirez V, Troth S, Muniappa N, Thudium D, Gerhold D, Holder DJ, Bobadilla NA, Marrer E, Perentes E, Cordier A, Vonderscher J, Maurer G, Goering PL, Sistare FD, Bonventre JV. Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat Biotechnol. 2010;28:478-85.

Wada Y, Kondo H, Itakura C. Peripheral neuropathy of dietary riboflavin deficiency in racing pigeons. J Vet Med Sci 1996;58:161–3.

Wang RW, Newton DJ, Scheri TD, Lu AY. Human cytochrome P450 3A4-catalyzed testosterone 6 beta-hydroxylation and erythromycin N-demethylation. Competition during catalysis. Drug Metab Dispos. 1997;25:502-7.

Wang T, Miller KW, Tu YY, Yang CS. Effects of riboflavin deficiency on metabolism of nitrosamines by rat liver microsomes. J Natl Cancer Inst. 1985;74:1291-7.

Wang Z. Physiologic and biochemical changes of mimetic aging induced by d- galactose in rat. Lab Anim Sci Admin. 1999;16:23-25.

Waterman MR, Gotoh O, Coon MJ, Estabrook RW, Gunsalus IC, Nebert DW. P450 superfamily: Update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics. 1996:6:1–42.

Waxman DJ, Dannan GA, Guengerich FP. Regulation of rat hepatic cytochrome P-450: age-dependent expression, hormonal imprinting, and xenobiotic inducibility of sex-specific isoenzymes. Biochemistry. 1985;24:4409-17.

Whitlock JP. Induction of cytochrome P4501A1. Annu. Rev. Pharmacol. Toxicol. 1999;39:103–25.

Williams-Ashman HG, Huggins C. Oxydation of reduced pyridine nucleotides in mammary gland and adipose tissue following treatment with polynuclear hydrocarbons. Med Exp Int J Exp Med. 1961;4:223-6.

Williams EA, Powers HJ, Rumsey RDE. Morphological changes in the rat small intestine in response to riboflavin depletion. Br J Nutr 1995;73:141–6.

Williams EA, Rumsey RDE, Powers HJ. An investigation into the reversibility of the morphological and cytokinetic changes seen in the small intestine of riboflavin deficient rats. Gut 1996;39:220–5.

Williams EA, Rumsey RD, Powers HJ. Cytokinetic and structural responses of the rat small intestine to riboflavin depletion. Br J Nutr. 1996;75:315-24.

Williams JR Jr, Grantham PH, Yamamoto RS, Weisburger JH. Effect of dietary riboflavin on azo dye reductase in liver and in bacteria of cecal contents of rats. Biochem Pharmacol. 1970;19:2523-5.

Xie W, Yeuh M, Radominska-Pandya A, Saini SP, Negishi Y, Bottroff BS. Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor. Proc Natl Acad Sci U S A. 2003;100:4150–5.

Xu Y, Wu T, Jin Y, Fu Z. Effects of age and jet lag on D-galactose induced aging process. Biogerontology. 2009;10:153-61.

Yang CS. Alterations of the aryl hydrocarbon hydroxylase system during riboflavin depletion and repletion. Arch Biochem Biophys. 1974;160:623-30.

Yamada Y, Merrill AH Jr, McCormick DB. Probable reaction mechanisms of flavokinase and FAD synthetase from rat liver. Arch Biochem Biophys. 1990;278:125-30.

Yao H, Wang XJ, Huang LP, Diao JX, Deng HZ. Effect of Oviductus Ranae on Cyclin D1, CDK6 and P15 expressions in the liver tissue of aged male rats. Nan Fang Yi Ke Da Xue Xue Bao. 2010;30:1044-6.

Yates CA, Evans GS, Powers HJ. Riboflavin deficiency: early effects on post weaning development of the duodenum in rats. Br J Nutr. 2001;86:593–9.

Yeung CK, Lang DH, Thummel KE, Rettie AE. Immunoquantitation of FMO1 in human liver, kidney, and intestine. Drug Metab Dispos. 2000;28:1107-11.

Yi ZJ, Fu YR, Li M, Gao KS, Zhang XG. Effect of LTA isolated from bifidobacteria on D-galactose-induced aging. Exp Gerontol. 2009;44:760-5.

Zafar KS, Inayat-Hussain SH, Ross D. A comparative study of proteasomal inhibition and apoptosis induced in N27 mesencephalic cells by dopamine and MG132. J Neurochem. 2007;102:913-21.

Zafar KS, Siegel D, Ross D. A potential role for cyclized quinones derived from dopamine, DOPA, and 3,4-dihydroxyphenylacetic acid in proteasomal inhibition. Mol Pharmacol. 2006;70:1079-86.

Zahid M, Gaikwad NW, Ali MF, Lu F, Saeed M, Yang L, Rogan EG, Cavalieri EL. Prevention of estrogen-DNA adduct formation in MCF-10F cells by resveratrol. Free Radic Biol Med. 2008;45:136-45.

Zaman Z, Verwilghen RL. Effect of riboflavin deficiency on activity of NADH-FMN oxidoreductase (ferriductase) and iron content of rat liver. Biochem Soc Trans. 1977;5:306-8.

Zanette D, Monaco HL, Zanotti G, Spadon P. Crystallisation of hen egg white riboflavin-binding protein. J Mol Biol. 1984;180:1185–7.

Zenser TV, Mattammal MB, Davis BB. Differential distribution of the mixed-function oxidase activities in rabbit kidney. J Pharmacol Exp Ther. 1978;207:719–25.

Zhang D, Liu G, Shi J, Zhang J. Coeloglossum viride var. bracteatum extract attenuates D-galactose and NaNO2 induced memory impairment in mice. J Ethnopharmacol. 2006;104:250-6.

Zhang X, Zhang BZ, Yang XL, Zhang WW, Li L. Behavior and memory changes in D-galactose-induced aging rat model. Chinese J Gerontol. 1996;16:230–2.

Zhu H, Jia Z, Mahaney JE, Ross D, Misra HP, Trush MA, Li Y. The highly expressed and inducible endogenous NAD(P)H:quinone oxidoreductase 1 in cardiovascular cells acts as a potential superoxide scavenger. Cardiovasc Toxicol. 2007;7:202-11.