UGT1A10 is responsible for SN-38 glucuronidation and its expression in human lung cancers.
BACKGROUND
We previously reported that upregulation of glucuronidation activity catalyzed by uridine 5'diphosphoglucuronosyltransferase (UGT) is one of the mechanisms associated with irinotecan hydrochloride/7-ethyl-10-hydroaxycamptothecin (CPT-11/SN-38) resistance. In order to extend this result to the clinical setting, it is important to elucidate the role of SN-38 glucuronidation by UGT1A isoforms in CPT-11/SN-38 resistance in vivo.


METHODS
We examined SN-38 glucuronidation activity in COS-7 cells transfected with full-length cDNAs for human UGT isoforms (UGT1A1, UGT1A3, UGT1A6 and UGT1A10). The gene expression levels of UGT isoforms were examined in lung cancer cell lines and 14 lung cancer samples by semi, quantitative RT-PCR.


RESULTS
Our HPLC assay results showed that both UGT1A1 and UGT1A10 are responsible for SN-38 glucuronidation. The levels of UGT1A1 and UGT1A10 expression in a CPT-11/SN-38-resistant cell line were increased compared to levels in the parent cell line. Furthermore, there was considerable intersubject variability in 14 lung cancer samples, but UGT1A1 and UGT1A10 expression levels were significantly correlated (r=0. 70, p=0.004). Our results suggest that not only UGT 1A1, but also UGT 1A10, plays an important role in detoxifying CPT-11/SN-38, leading to resistance to CPT-11/SN-38 in lung cancer.
Oguri
Tetsuya
T
Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. t-oguri@med.nagoya-cu.ac.jp
Takahashi
Toshiaki
T
Miyazaki
Mitsuru
M
Isobe
Takeshi
T
Kohno
Nobuoki
N
Mackenzie
Peter I
PI
Fujiwara
Yasuhiro
Y
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D019556:COS Cells; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000378:metabolism* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D002851:Chromatography, High Pressure Liquid; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D020719:Glucuronides / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008875:Middle Aged
C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D000972:Antineoplastic Agents, Phytogenic; D020719:Glucuronides; D000077146:Irinotecan; C476725:bilirubin uridine-diphosphoglucuronosyl transferase 1A10; D014453:Glucuronosyltransferase; D002166:Camptothecin