UDP-glucuronosyltransferase 1A10 (
UGT1A10) is an extrahepatic
enzyme expressed in aerodigestive tract tissues that exhibits significant glucuronidation activity against the important procarcinogenic
benzo(a)pyrene (BaP) metabolite, BaP-trans-7,8-dihydrodiol (BPD), and the
UGT1A10 codon 139 (Glu>Lys) polymorphism was previously implicated in risk for orolaryngeal
cancer by Elahi et al. in their 2003 study. To better assess the potential role of
UGT1A10 in risk for tobacco-related
cancers, the glucuronidation activity of
UGT1A10 was compared with that of other known UGT
enzymes against selected
polycyclic aromatic hydrocarbons, and the effects of the
codon 139 polymorphism on
UGT1A10 function were examined in vitro.
UGT1A10 exhibited considerably more glucuronidation activity as determined by Vmax/Km 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 using Vmax could not be performed against family 2B UGTs,
UGT1A10 exhibited a 1.7- to 254-fold lower Km than active family 2B UGTs against
3-OH-BaP, 7-OH-BaP, and 1-OH-pyrene. A significantly (p < 0.01) higher Vmax/Km was observed for homogenates from wild-type UGT1A10139Glu-overexpressing 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 Vmax/Km was observed for homogenates from wild-type UGT1A10139Glu-overexpressing cells against 1-OH-pyrene. Significant differences in Km were observed for homogenates from wild-type UGT1A10139Glu-overexpressing cells against 1-OH-pyrene (p < 0.05) and
3-OH-BaP (p < 0.01). Reverse transcription-polymerase chain reaction of total lung
RNA showed low levels of
UGT1A10 expression in human lung tissue. Together, these studies implicate
UGT1A10 as an important detoxifier of
polycyclic aromatic hydrocarbons in humans and that the
UGT1A10 codon 139 polymorphism may be an important determinant in risk for tobacco-related
cancers.