The UDP-Glucuronosyltransferase 2B17 Gene Deletion Polymorphism: Sex-Specific Association with Urinary 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol Glucuronidation Phenotype and Risk for Lung Cancer

Abstract

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent and abundant procarcinogen found in tobacco smoke, and glucuronidation of its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), by UDP-glucuronosyltransferases (UGT) including UGT2B17 is an important mechanism for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone detoxification. Both copies of the UGT2B17 gene are deleted in f10% of Whites and the deletion is associated with a reduction in NNAL glucuronidation activity in vitro. In this study, we examined the effects of the UGT2B17 deletion (0/0) on NNAL glucuronidation rates in a sample of 82 healthy cigarette smokers and further examined its effects on lung cancer risk in a separate case-control study. In the healthy smokers study, a lower urinary ratio of NNAL-glucuronide to NNAL was observed in women with the UGT2B17 deletion (0/0) as compared with women with either the wild-type or heterozygous genotypes (P = 0.058).There were no significant differences in this ratio by genotype in men (P = 0.597). In the case-control study of 398 lung cancer patients and 697 community controls, the UGT2B17 deletion (0/0) was associated with a significant increase in risk of lung cancer in women (odds ratio, 2.0; 95% confidence interval, 1.01-4.0). The risk for the subset of women with lung adenocarcinoma was 2.8 (95% confidence interval, 1.2-6.3). The deletion was not associated with other lung histologic types in women and was not associated with the risk for any lung histologic types in men. The association of the UGT2B17 deletion with increased lung adenocarcinoma in women is consistent with its association with decreased NNAL glucuronidation rates in women and with studies showing that NNAL is a selective inducer of lung adenocarcinoma in experimental animals. (Cancer Epidemiol Biomarkers Prev 2007;16(4):823 -8)

UGT2B Gene Expression Analysis in Multiple Tobacco Carcinogen-Targeted Tissues

“…All UGT2B isoforms were detected in all human liver tissue specimens examined, as previously reported by other groups (Nakamura et al, 2008a;Izukawa et al, 2009;Ohno and Nakajin, 2009;Court et al, 2012). Only UGT2B17 exhibited no expression in four of the liver specimens examined, likely because those specimens were from subjects exhibiting the homozygous genotype for the prevalent (30% in Caucasians) UGT2B17 wholegene deletion allele (Wilson et al, 2004;Lazarus et al, 2005;Gallagher et al, 2007). The relative levels of hepatic expression were highest for UGT2B4, followed by UGT2B7 .…”

“…With the exception of human tongue, UGT2B17 was expressed at the highest or second-highest level of any of the UGT2B genes. UGT2B17 exhibits the highest activity of all UGTs in forming the O-glucuronide of NNAL (Lazarus et al, 2005), and the UGT2B17 gene deletion is associated with lung adenocarcinoma risk (Gallagher et al, 2007), a pattern consistent with the high levels of UGT2B17 expression observed in lung in the present study and with NNAL's induction of lung adenocarcinoma in rodent models (Rivenson et al, 1988;Hecht, 1998). While no studies have examined the role of the UGT2B17 deletion in cancer susceptibility within the aerodigestive tract, relatively high levels of UGT2B17 expression in larynx, tonsil, esophagus, and floor of mouth suggests that the UGT2B17 deletion may play a similarly important etiologic role in the induction of cancers within these tissues.…”

Genetic susceptibility of lung cancer associated with common variants in the 3′ untranslated regions of the adenosine triphosphate‐binding cassette B1 (ABCB1) and ABCC1 candidate transporter genes for carcinogen export

“…12 It also has been reported that polymorphisms in the phase II conjugation enzyme genes, such as uridine diphosphate glucuronosyltransferase 1 family, polypeptide A7 (UGT1A7) and UGT2B17, have implications in lung cancer etiology. 13,14 However, few studies have addressed the relation between genetic predisposition to lung cancer and polymorphisms in phase III transporter genes.…”

“Target-Site” Drug Metabolism and Transport

“…Pharmacogenetic variability in XMEs can impact their role in the overall disposition of drugs and xenobiotics, and may predict the clinical outcome. An example is the UGT2B17 gene deletion, which was found to correlate with increased incidence of lung adenocarcinoma in women, possibly due to decreased glucuronidation (detoxification) of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (Gallagher et al, 2007).…”

“…The key P450, UGT, SULT, and drug transporters known to be expressed in the human lung are depicted (PEPT, peptide transporter; SLCO, solute carrier organic anion transporter; OATP, organic anion-transporting polypeptide). Data compiled from previously published reports (Gallagher et al, 2007;Somers et al, 2007;Bosquillon, 2010;Anttila et al, 2011;Sharan and Nagar, 2013;Jones and Lazarus, 2014).…”