Identification of cyclosporine A and tacrolimus glucuronidation in human liver and the gastrointestinal tract by a differentially expressed UDP-glucuronosyltransferase: UGT2B7.
OBJECTIVE
The oral administration of the major transplant immunosuppressants cyclosporine A and tacrolimus leads to unpredictable drug levels requiring drug monitoring. Hepatic and extrahepatic metabolism of cyclosporine A and tacrolimus by cytochrome P450 proteins has been analyzed but metabolism and inactivation by glucuronidation has not been investigated.


METHODS
Cyclosporine A and tacrolimus glucuronidation was measured in hepatic and gastrointestinal microsomal protein, and with 11 recombinant hepatic and extrahepatic family 1 and 2 UDP-glucuronosyltransferases. UDP-glucuronosyltransferase transcripts were determined by polymerase chain reaction.


RESULTS
Significant cyclosporine and tacrolimus glucuronidation activity was present in endoplasmic reticulum from liver, duodenum, jejunum, ileum and colon, but was absent in stomach. Specific cyclosporine A glucuronidation activity was highest in liver and colon, tacrolimus glucuronidation was highest in liver. Analyses using recombinant UDPglucuronosyltransferases identified UGT2B7 as a human UDP-glucuronosyltransferase with specific activity toward cyclosporine A and tacrolimus. The hepato-gastrointestinal distribution of immunosuppressant glucuronidation activity corresponded to the differential expression pattern of UGT2B7 mRNA.


CONCLUSIONS
This study provides conclusive evidence of hepatic and extrahepatic immunosuppressant glucuronidation by human UGT2B7 which was identified to be differentially expressed in the human hepatogastrointestinal tract. Hepatic and extrahepatic glucuronidation may influence the therapeutic efficacy of transplant immunosuppressants.
Strassburg
C P
CP
Department of Gastroenterology and Hepatology, Medical School of Hannover, Germany. strassburg.christian@mh-hannover.de
Barut
A
A
Obermayer-Straub
P
P
Li
Q
Q
Nguyen
N
N
Tukey
R H
RH
Manns
M P
MP
D000284:Administration, Oral; D016572:Cyclosporine / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D004064:Digestive System / Q000378:metabolism*; D015870:Gene Expression; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016559:Tacrolimus / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D014018:Tissue Distribution
D020719:Glucuronides; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016572:Cyclosporine; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D016559:Tacrolimus