PMID- 18474676
OWN - NLM
STAT- MEDLINE
DCOM- 20080926
LR  - 20121115
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 36
IP  - 8
DP  - 2008 Aug
TI  - UDP-glucuronosyltransferase 1A6 is the major isozyme responsible for 
      protocatechuic aldehyde glucuronidation in human liver microsomes.
PG  - 1562-9
LID - 10.1124/dmd.108.020560 [doi]
AB  - Glucuronidation is an important pathway in the metabolism of protocatechuic 
      aldehyde (3,4-dihydroxybenzaldehyde, PAL). However, the metabolites and primary 
      UDP-glucuronosyltransferase (UGT) isozymes responsible for PAL glucuronidation 
      remain to be determined in human. Here, we characterized PAL glucuronidation by 
      human liver microsomes (HLMs), human intestine microsomes (HIMs), and 12 
      recombinant UGT (rUGT) isozymes to identify what kinds of metabolites are present 
      and which human UGT isozymes are involved. Two metabolites (M-1 and M-2) were 
      detected in reactions catalyzed by HLMs, HIMs, rUGT1A6, and rUGT1A9 and were 
      identified as monoglucuronides by liquid chromatography-mass spectrometry. A 
      kinetic study showed that PAL glucuronidation by rUGT1A6, rUGT1A9, HIMs, and HLMs 
      followed Michaelis-Menten kinetics. The K(m) values of HLMs, HIMs, rUGT1A6, and 
      rUGT1A9 for PAL glucuronidation were as follows: 432.7 +/- 24.5, 626.9 +/- 49.2, 
      367.5 +/- 25.1, and 379.9 +/- 42.5 microM for M-1 and 336.7 +/- 15.3, 494.3 +/- 
      48.7, 211.4 +/- 13.4, and 238.5 +/- 26.2 microM for M-2, respectively. The PAL 
      glucuronidation activity was significantly correlated with UGT1A6 activity rather 
      than with UGT1A9 activity from 15 individual HLMs. A chemical inhibition study 
      showed that the IC(50) for phenylbutazone inhibition of PAL glucuronidation was 
      similar in HLMs (61.9 +/- 7.9 microM) compared with rUGT1A6 (45.3 +/- 7.7 
      microM). In contrast, androsterone inhibited rUGT1A9-catalyzed and HLM-catalyzed 
      PAL glucuronidation with IC(50) values of 27.1 +/- 3.8 and > 500 microM, 
      respectively. In combination, we identified UGT1A6 as the major isozyme 
      responsible for PAL glucuronidation in HLMs.
FAU - Liu, Hui-Xin
AU  - Liu HX
AD  - Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical 
      Physics, Chinese Academy of Sciences, No. 457 Zhongshan Rd., Dalian 116023 China.
FAU - Liu, Yong
AU  - Liu Y
FAU - Zhang, Jiang-Wei
AU  - Zhang JW
FAU - Li, Wei
AU  - Li W
FAU - Liu, Hong-Tao
AU  - Liu HT
FAU - Yang, Ling
AU  - Yang L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080512
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Benzaldehydes)
RN  - 0 (Catechols)
RN  - 0 (Glucuronides)
RN  - 0 (Isoenzymes)
RN  - 4PVP2HCH4T (protocatechualdehyde)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
SB  - IM
MH  - Benzaldehydes/*pharmacokinetics
MH  - Biotransformation
MH  - Catechols/*pharmacokinetics
MH  - Chromatography, High Pressure Liquid
MH  - Glucuronides/*metabolism
MH  - Glucuronosyltransferase/*metabolism
MH  - Humans
MH  - Isoenzymes/*metabolism
MH  - Microsomes, Liver/*enzymology/metabolism
MH  - Spectrophotometry, Ultraviolet
EDAT- 2008/05/14 09:00
MHDA- 2008/09/27 09:00
CRDT- 2008/05/14 09:00
PHST- 2008/05/14 09:00 [pubmed]
PHST- 2008/09/27 09:00 [medline]
PHST- 2008/05/14 09:00 [entrez]
AID - dmd.108.020560 [pii]
AID - 10.1124/dmd.108.020560 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2008 Aug;36(8):1562-9. doi: 10.1124/dmd.108.020560. Epub 2008 
      May 12.