PT  - JOURNAL ARTICLE
AU  - Nikhil K. Basu
AU  - Labanyamoy Kole
AU  - Shigeki Kubota
AU  - Ida S. Owens
TI  - HUMAN UDP-GLUCURONOSYLTRANSFERASES SHOW ATYPICAL METABOLISM OF MYCOPHENOLIC ACID AND INHIBITION BY CURCUMIN
AID  - 10.1124/dmd.32.7.768
DP  - 2004 Jul 01
TA  - Drug Metabolism and Disposition
PG  - 768--773
VI  - 32
IP  - 7
4099  - http://dmd.aspetjournals.org/content/32/7/768.short
4100  - http://dmd.aspetjournals.org/content/32/7/768.full
SO  - Drug Metab Dispos2004 Jul 01; 32
AB  - Although the promising immunosuppressant, mycophenolic acid (MPA), has many desirable properties and is widely prescribed for organ transplant recipients, its high oral dosage requirement is not understood. Whereas previous Northern blot analysis by Basu and colleagues (2004) located the mRNAs encoding MPA primary metabolizers, UDP-glucuronosyltransferases (UGTs) 1A7, 1A8, 1A9, and 1A10, in human gastrointestinal (GI) tissues, in situ hybridization analysis of mRNAs found that the isozymes were restricted to the mucosal layer of various GI organs. Concomitantly, MPA was glucuronidated by microsomes isolated from normal adjoining specimens. Microsomal studies showed the highest relative rates of metabolism in esophagus, ileum, duodenum, colon, and stomach at pH 6.4; only esophagus showed high pH 7.6 activity. Properties of the recombinant UGTs indicate that MPA is metabolized with pH 6.4 or 7.6 optimum. Activity for 1A7 and 1A9 increased with increasing concentrations up to 2.4 mM, with parallel production of both ether- and acylglucuronides; similarly, 1A8 and 1A10 reached plateaus at 1.6 mM, producing both glucuronides. Km values were 250 to 550 μM. Between 400 and 1600 μM MPA, isozymes generated between 15 and 42% of the acylglucuronides. In effect, high Km values (MPA) are associated with high concentrations to achieve saturation kinetics. Finally, transient inhibition of UGTs in human LS180 colon cells and mouse duodenum by the dietary agent, curcumin, has implications for in vivo pretreatment to reduce MPA glucuronidation to increase the therapeutic index. The American Society for Pharmacology and Experimental Therapeutics