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Vol. 60, Issue 5, 1040-1048, November 2001
Graduate School of Pharmaceutical Sciences, Kyushu University,
Maidashi, Higashi-ku, Fukuoka, Japan (Y.I, A.M., R.W., K.T., M.T.,
Y.Y.-N., K.Y, M.T., D.M., K.O.); and Hokkaido National Industrial
Research Institute, Sapporo, Japan (S.O.)
Although UDP-glucuronosyltransferases (UGTs) act as an important
detoxification system for many endogenous and exogenous compounds, they
are also involved in the metabolic activation of morphine to form
morphine-6-glucuronide (M-6-G). The cDNAs encoding guinea pig liver
UGT2B21 and UGT2B22, which are intimately involved in M-6-G formation,
have been cloned and characterized. Although some evidence suggests
that UGTs may function as oligomers, it is not known whether
hetero-oligomer formation leads to differences in substrate
specificity. In this work, evidence for a functional hetero-oligomer
between UGT2B21 and UGT2B22 is provided by studies on the
glucuronidation of morphine in transfected COS-7 cells. Cells
transfected with UGT2B21 cDNA catalyzed mainly morphine-3-glucuronide formation although M-6-G was also formed to some extent. In contrast, cells transfected with UGT2B22 cDNA did not show any significant activity toward morphine. When UGT2B21 and UGT2B22 were expressed simultaneously in different ratios in COS-7 cells, extensive M-6-G formation was observed. This stimulation of M-6-G formation was not
observed, however, when microsomes containing UGT2B21were mixed with
those containing UGT2B22 in the presence of detergent. Furthermore,
this effect was not very marked when human UGT1A1 and UGT2B21 were
coexpressed in COS-7 cells. This is the first report suggesting that
UGT hetero-oligomer formation leads to altered substrate specificity.
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