Received for publication December 27, 2005.
Revised February 24, 2006.
Accepted for publication February 28, 2006.

IMPORTANCE OF UDP-GLUCURONOSYLTRANSFERASE 1A10 (UGT1A10) IN THE DETOXIFICATION OF POLYCYCLIC AROMATIC HYDROCARBONS: DECREASED GLUCURONIDATIVE ACTIVITY OF THE UGT1A10^139LYS ISOFORM

Abstract

UGT1A10 is an extra-hepatic enzyme expressed in aerodigestive tract tissues that exhibits significant glucuronidation activity against the important procarcinogenic benzo(a)pyrene (BaP) metabolite, BaP-7,8-dihydrodiol (BPD), and the UGT1A10 codon 139 (Glu>Lys) polymorphism was previously implicated in risk for orolaryngeal cancer (Elahi et al, Cancer 15:872-880; 2003). To better assess the potential role of UGT1A10 in risk for tobacco-related cancers, the glucuronidation activity of UGT1A10 was compared to that of other known UGT enzymes against selected polycyclic aromatic hydrocarbons and the effects of the codon 139 polymorphism on UGT1A10 function was examined in vitro. UGT1A10 exhibited considerably more glucuronidation activity as determined by V_max/K_m against 3-hydroxy (OH)-BaP, 7-OH-BaP, 9-OH-BaP and 1-OH-pyrene than any other UGT1A family member. Although a kinetic comparison utilizing V_max could not be performed against family 2B UGTs, UGT1A10 exhibited a 1.7-254-fold lower K_m than active family 2B UGTs against 3-OH-BaP, 7-OH-BaP and 1-OH-pyrene. A significantly (p<0.01) higher V_max/K_m was observed for homogenates from wild-type UGT1A10^139Glu-over-expressing cells against all four BaP metabolites tested (3-OH-BaP, 7-OH-BaP, 9-OH-BaP and BPD). A similarly significant (p<0.05) increase in V_max/K_m was observed for homogenates from wild-type UGT1A10^139Glu-over-expressing cells against 1-OH-pyrene. Significant differences in K_m were observed for homogenates from wild-type UGT1A10^139Glu-over-expressing cells against 1-OH-pyrene (p<0.05) and 3-OH-BaP (p<0.01). RT-PCR of total lung RNA demonstrated low levels of UGT1A10 expression in human lung tissue. Together, these studies implicate UGT1A10 as an important detoxifier of PAHs in humans and that the UGT1A10 codon 139 polymorphism may be an important determinant in risk for tobacco-related cancers.

Key words: enzyme kinetics, glucuronidation, liver microsomes, lung cancer, pharmacogenetics, pharmacokinetics, polycyclic aromatic hydrocarbons, polymorphisms, UDP glucuronyltransferases

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