Flavonoids of Cynara scolymus Possess Potent Xanthinoxidase Inhibitory Activity in vitro but are Devoid of Hypouricemic Effects in Rats after Oral Application

 

 Buy Article Permissions and Reprints

Abstract

Artichoke (Cynara scolymus L.) leaves have been historically used for the treatment of hyperuricemia and gout, however whether artichoke is truly efficacious for this indication, is still a matter of debate. Thus, the goal of the present study was first to examine the xanthine oxidase (XO) inhibitory activity of an artichoke leaf extract (ALE) and some of its main compounds in vitro and then further test potentially active substances for possible hypouricemic effects using an in vivo rat model. The in vitro study showed that ALE inhibited XO with only minimal inhibitory action (< 5 %) at 100 μg/mL. However, when selected compounds were tested, the caffeic acid derivatives revealed a weak XO inhibitory effect with IC₅₀ > 100 μM. From the tested flavones the aglycone luteolin potently inhibited XO with an IC₅₀ value of 1.49 μM. Luteolin 7-O-glucoside and luteolin 7-O-glucuronide showed lower XO inhibition activities with IC₅₀ values of 19.90 μM and 20.24 μM, respectively. However, oral administration of an aqueous ALE, luteolin, and luteolin 7-O-glucoside did not produce any observable hypouricemic effects after acute oral treatment in potassium oxonate-treated rats. After intraperitoneal injection of luteolin a decrease in uric acid levels was detected suggesting that the hypouricemic effects of luteolin are due to its original form rather than its metabolites produced by the gut flora. In conclusion, an aqueous ALE, caffeic acid derivatives and flavones exerted XO inhibitory effects in vitro but a hypouricemic activity could not be confirmed after oral administration.

Abbreviations

ALE:Artichoke leaf extract

CMC-Na:carboxymethylcellulose sodium salt

DAD:photodiode array detector

PO:Potassium oxonate

RP-HPLC:reverse phase high performance liquid chromatography

XO:xanthine oxidase

References

• 1 Roddy E, Zhang W, Doherty M. The changing epidemiology of gout.  Nat Clin Pract Rheumatol. 2007;  3 443-9
  CrossrefPubMedGoogle Scholar
• 2 Emmerson B T. The use of the xanthine oxidase inhibitor, allopurinol, in the control of hyperuricaemia, gout and uric acid calculi.  Australas Ann Med. 1967;  16 205-14
  PubMedGoogle Scholar
• 3 Falasca G F. Metabolic diseases: gout.  Clin Dermatol. 2006;  24 498-508
  PubMedGoogle Scholar
• 4 Fritsch P O, Sidoroff A. Drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis.  Am J Clin Dermatol. 2000;  1 349-60
  PubMedGoogle Scholar
• 5 Horiuchi H, Ota M, Nishimura S, Kaneko H, Kasahara Y, Ohta T. et al . Allopurinol induces renal toxicity by impairing pyrimidine metabolism in mice.  Life Sci. 2000;  66 2051-70
  CrossrefPubMedGoogle Scholar
• 6 Hammer B, Link A, Wagner A, Bohm M. Hypersensitivity syndrome during therapy with allopurinol in asymptomatic hyperuricemia with a fatal outcome.  Dtsch Med Wochenschr. 2001;  126 1331-4
  Article in Thieme ConnectPubMedGoogle Scholar
• 7 Wegener T, Fintelmann V. Pharmacological properties and therapeutic profile of artichoke (Cynara scolymus L.).  Wien Med Wochenschr. 1999;  149 241-7
  PubMedGoogle Scholar
• 8 Gebhardt R. Inhibition of cholesterol biosynthesis in HepG2 cells by artichoke extracts is reinforced by glucosidase pretreatment.  Phytother Res. 2002;  16 368-72
  CrossrefPubMedGoogle Scholar
• 9 Englisch W, Beckers C, Unkauf M, Ruepp M, Zinserling V. Efficacy of Artichoke dry extract in patients with hyperlipoproteinemia.  Arzneimittelforschung. 2000;  50 260-5
  PubMedGoogle Scholar
• 10 Adzet T, Camarasa J, Laguna J C. Hepatoprotective activity of polyphenolic compounds from Cynara scolymus against CCl4 toxicity in isolated rat hepatocytes.  J Nat Prod. 1987;  50 612-7
  CrossrefPubMedGoogle Scholar
• 11 Clifford M. Chlorogenic acids and other cinnamates-nature, occurence, dietary burden, absorption and metabolism.  J Sci Food Agric. 2000;  80 1033-43
  CrossrefPubMedGoogle Scholar
• 12 Schutz K, Kammerer D, Carle R, Schieber A. Identification and quantification of caffeoylquinic acids and flavonoids from artichoke (Cynara scolymus L.) heads, juice, and pomace by HPLC-DAD-ESI/MS(n).  J Agric Food Chem. 2004;  52 4090-6
  CrossrefPubMedGoogle Scholar
• 13 Scalbert A, Manach C, Morand C, Remesy C, Jimenez L. Dietary polyphenols and the prevention of diseases.  Crit Rev Food Sci Nutr. 2005;  45 287-306
  CrossrefPubMedGoogle Scholar
• 14 Nagao A, Seki M, Kobayashi H. Inhibition of xanthine oxidase by flavonoids.  Biosci Biotechnol Biochem. 1999;  63 1787-90
  PubMedGoogle Scholar
• 15 Beyer G, Melzig M F. Effects of selected flavonoids and caffeic acid derivatives on hypoxanthine-xanthine oxidase-induced toxicity in cultivated human cells.  Planta Med. 2003;  69 1125-9
  Article in Thieme ConnectPubMedGoogle Scholar
• 16 Gongora L, Manez S, Giner R M, Recio Medel C, Schinella G, Rios J L. Inhibition of xanthine oxidase by phenolic conjugates of methylated quinic acid.  Planta Med. 2003;  69 396-401
  Article in Thieme ConnectPubMedGoogle Scholar
• 17 Stavric B, Clayman S, Gadd R E, Hebert D. Some in vivo effects in the rat induced by chlorprothixene and potassium oxonate.  Pharmacol Res Commun. 1975;  7 117-24
  PubMedGoogle Scholar
• 18 Chan W S, Wen P C, Chiang H C. Structure-activity relationship of caffeic acid analogues on xanthine oxidase inhibition.  Anticancer Res. 1995;  15 703-7
  PubMedGoogle Scholar
• 19 Ding Z, Dai Y, Wang Z. Hypouricemic action of scopoletin arising from xanthine oxidase inhibition and uricosuric activity.  Planta Med. 2005;  71 183-5
  Article in Thieme ConnectPubMedGoogle Scholar
• 20 Kong L, Zhou J, Wen Y, Li J, Cheng C H. Aesculin possesses potent hypouricemic action in rodents but is devoid of xanthine oxidase/dehydrogenase inhibitory activity.  Planta Med. 2002;  68 175-8
  Article in Thieme ConnectPubMedGoogle Scholar
• 21 Zhu J X, Wang Y, Kong L D, Yang C, Zhang X. Effects of Biota orientalis extract and its flavonoid constituents, quercetin and rutin on serum uric acid levels in oxonate-induced mice and xanthine dehydrogenase and xanthine oxidase activities in mouse liver.  J Ethnopharmacol. 2004;  93 133-40
  CrossrefPubMedGoogle Scholar
• 22 Iwamoto T, Yoshiura M, Iriyama K. A simple, rapid and sensitive method for the determination of rat serum uric acid by reversed-phase high-performance liquid chromatography with electrochemical detection.  J Chromatogr. 1983;  278 156-9
  PubMedGoogle Scholar
• 23 Hall I H, Scoville J P, Reynolds D J, Simlot R, Duncan P. Substituted cyclic imides as potential anti-gout agents.  Life Sci. 1990;  46 1923-7
  CrossrefPubMedGoogle Scholar
• 24 Noro T, Oda Y, Miyase T, Ueno A, Fukushima S. Inhibitors of xanthine oxidase from the flowers and buds of Daphne genkwa. .  Chem Pharm Bull (Tokyo). 1983;  31 3984-7
  PubMedGoogle Scholar
• 25 Shimoi K, Okada H, Furugori M, Goda T, Takase S, Suzuki M, Hara Y, Yamamoto H, Kinae N. Intestinal absorption of luteolin and luteolin 7-O-beta-glucoside in rats and humans.  FEBS Lett. 1998;  438 220-4
  CrossrefPubMedGoogle Scholar
• 26 Kong A N, Owuor E, Yu R, Hebbar V, Chen C, Hu R. et al . Induction of xenobiotic enzymes by the MAP kinase pathway and the antioxidant or electrophile response element (ARE/EpRE).  Drug Metab Rev. 2001;  33 255-71
  CrossrefPubMedGoogle Scholar
• 27 Boersma M G, van der Woude H, Bogaards J, Boeren S, Vervoort J, Cnubben N H. et al . Regioselectivity of phase II metabolism of luteolin and quercetin by UDP-glucuronosyl transferases.  Chem Res Toxicol. 2002;  15 662-70
  CrossrefPubMedGoogle Scholar
• 28 Wittemer S M, Ploch M, Windeck T, Muller S C, Drewelow B, Derendorf H. et al . Bioavailability and pharmacokinetics of caffeoylquinic acids and flavonoids after oral administration of Artichoke leaf extracts in humans.  Phytomedicine. 2005;  12 28-38
  CrossrefPubMedGoogle Scholar
• 29 Winter J, Moore L H, Dowell VR J r, Bokkenheuser V D. C-ring cleavage of flavonoids by human intestinal bacteria.  Appl Environ Microbiol. 1989;  55 1203-8
  PubMedGoogle Scholar
• 30 Lukas G, Brindle S D, Greengard P. The route of absorption of intraperitoneally administered compounds.  J Pharm Exp Ther. 1971;  178 562 - 6
  PubMedGoogle Scholar

Dr. Veronika Butterweck

College of Pharmacy

Department of Pharmaceutics

University of Florida

Gainesville

P.O. Box 100494

Florida 32610

USA.

Phone: +1-352-273-7859

Fax: +1-352-273-7854

Email: butterwk@cop.ufl.edu

• Supplementary Material