KUNDU , RAKESH and DASGUPTA , SUMAN and BISWAS , ANINDITA and BHATTACHARYA , SUSHMITA and PAL , BIKAS C and BHATTACHARYA , SHELLEY and RAO , P G and BORDOLOI , M J and BHATTACHARYA , SAMIR (2011) Carlinoside reduces hepatic bilirubin accumulation by stimulating bilirubin-UGT activity through Nrf2 gene expression. Biochemical Pharmacology, 82. pp. 1186-1197.

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Abstract

Accu mulati on of biliru bin, prima rily because of its insol ubilit y, has bee n found to be associa ted with liver disea ses includ ing jaundice . Free bilir ubin is insol uble; its glucuro nidation by bilirubin -UGT enz yme (UGT1 A1) makes it soluble and elimina tes it throu gh urine and fae ces. Taki ng CCl 4 induced ra t liver dysfun ction m odel, we demonst rated that supp ression of UGT1A 1 activity in ra t liv er increa sed ser um biliru bin level wh ich could be reve rsed by carl inoside (Cln), a flavone glyc oside. Alth ough Cln is a flavone compou nd, it escaped self-glucu ronid ation in the intestin e and readily absorbe d. Kineti c stud y of mic rosoma l UGT1A 1 from HepG 2 cells sugg ested that Cln enhan ced enz yme activity by increa sing V max with out alterin g K m. This altered V max was foun d to be due to UGT1A 1 ove rexpre ssion by Cln wh ich wa s obser ved in both HepG 2 and rat prima ry hepa tocytes . Sin ce Nrf2 is the transc ription factor of UG T1A1, we exam ined whethe r Cln effe ct on UG T1A1 overexp ression is media ted th rough Nrf2. In Nrf2 knock -out cells, Cln cou ld not eleva te UG T1A1 activity indica ting Nrf2 to be its target. Cln signific antly increas ed Nrf2 ge ne expr ession in HepG2 cells wh ich was subse quently locali zed in nuclear region . Resu lts from Ch IP assa y show ed that Cln mar kedly augm ented Nrf2 bindi ng to UGT1A 1 prom oter that con sequentl y enhan ced report er act ivity. Our findings therefor e show that Cln upreg ulated Nr f2 gene expr ession, incr eased its nu clear tran slocation and stimula ted UGT1A 1 prom oter act ivity. Tota l outc ome of these even ts brought about a signific ant increase of biliru bin glucur onida tion. Cln ther efore could be a wor thy choice to int ervene hype rbilir ubinemi a due to liv er dysfunc tion.

Item Type:	Article
Subjects:	Chemistry > Organic Chemistry
Divisions:	UNSPECIFIED
Depositing User:	Dr. PK Barooah
Date Deposited:	28 Dec 2011 09:15
Last Modified:	28 Dec 2011 09:15
URI:	http://neist.csircentral.net/id/eprint/147

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