title: Sex differences in UDP-glucuronosyltransferase 2B17 expression and activity.
abstract: UDP-glucuronosyltransferases (UGTs) are enzymes involved in the metabolism of steroid hormones, carcinogens, cancer chemotherapy agents, and addictive agents from cigarettes. Because the UGT2B family of genes has been linked to hormonal regulation in human cell lines in vitro, we hypothesized that there may be sex-related differences in the expression and activity of these genes in human tissues. To evaluate whether there are sex differences in UGT2B expression and activity, we examined 103 normal human liver specimens for UGT2B expression by real-time polymerase chain reaction and in vitro glucuronidation activities in human liver microsomes (HLM). Men exhibited an approximately 4-fold higher level of expression of UGT2B17 than women (p = 0.007). Consistent with the increased expression of UGT2B17 in men, HLM from men also had a higher level of glucuronidation activity than HLM from women against three UGT2B17 substrates: 3-fold higher for 17-dihydroexemestane (p = 0.002); 3-fold higher for 3-hydroxycotinine (p < 0.001); and 1.5-fold higher for suberoylanilide hydroxamic acid (p = 0.014). When we stratified by UGT2B17 gene deletion genotype, similar patterns were observed for all three substrates, with HLM from men with the UGT2B17 (+/+) or (+/0) genotypes exhibiting significantly higher levels of glucuronidation activity against all three substrates compared with HLM from women. These data suggest that men have a higher amount of UGT2B17 glucuronidation activity then women. This sex difference in UGT2B17 gene expression and corresponding protein activity could potentially result in different levels of carcinogen detoxification or drug elimination in men versus women.
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, 500 University Drive, CH69, Hershey, PA 17033, USA.
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Gallagher
authors.forename: Renee M
authors.initials: RM
authors.lastname: Balliet
authors.forename: Dongxiao
authors.initials: D
authors.lastname: Sun
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Philip
authors.initials: P
authors.lastname: Lazarus
mesh_terms: D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger / Q000032:analysis; D012727:Sex Characteristics
chemical_list: D020719:Glucuronides; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human
references.citation: Breast Cancer Res. 2004;6(6):246-54
references.pmid: 15535854
references.citation: J Pharmacol Exp Ther. 2004 Aug;310(2):656-65
references.pmid: 15044558
references.citation: Cancer Res. 2004 Feb 1;64(3):1190-6
references.pmid: 14871856
references.citation: J Exp Med. 2003 May 19;197(10):1279-89
references.pmid: 12743171
references.citation: Pharm Res. 1997 Sep;14(9):1115-21
references.pmid: 9327435
references.citation: J Steroid Biochem Mol Biol. 1998 Apr;65(1-6):301-10
references.pmid: 9699884
references.citation: Genomics. 2004 Oct;84(4):707-14
references.pmid: 15475248
references.citation: Annu Rev Pharmacol Toxicol. 2000;40:581-616
references.pmid: 10836148
references.citation: J Clin Endocrinol Metab. 2004 Oct;89(10):5222-32
references.pmid: 15472229
references.citation: J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):413-23
references.pmid: 10419020
references.citation: Biochemistry. 2001 Apr 3;40(13):3869-81
references.pmid: 11300766
references.citation: Cancer Res. 2009 Apr 1;69(7):2981-9
references.pmid: 19318555
references.citation: J Steroid Biochem Mol Biol. 2000 Oct;74(3):149-55
references.pmid: 11086234
references.citation: Endocrinology. 2006 Nov;147(11):5431-42
references.pmid: 16887906
references.citation: Endocrinology. 2006 Aug;147(8):3843-50
references.pmid: 16690804
references.citation: J Pharmacol Exp Ther. 1980 Oct;215(1):86-91
references.pmid: 7452494
references.citation: Mol Pharmacol. 2009 Aug;76(2):425-39
references.pmid: 19487245
references.citation: Cancer Epidemiol Biomarkers Prev. 2007 Apr;16(4):823-8
references.pmid: 17416778
references.citation: Endocrinology. 1997 Jul;138(7):2998-3005
references.pmid: 9202245
references.citation: Drug Metab Dispos. 2002 Nov;30(11):1257-65
references.pmid: 12386133
references.citation: Pharm Res. 1999 Feb;16(2):191-7
references.pmid: 10100302
references.citation: Drug Metab Pharmacokinet. 2006 Oct;21(5):357-74
references.pmid: 17072089
references.citation: Drug Metab Dispos. 2007 Jan;35(1):121-7
references.pmid: 17050650
references.citation: Trends Endocrinol Metab. 2003 Dec;14(10):473-9
references.pmid: 14643063
references.citation: DNA Cell Biol. 1997 Oct;16(10):1143-54
references.pmid: 9364925
references.citation: Pharmacogenet Genomics. 2010 Oct;20(10):575-85
references.pmid: 20697310
references.citation: Oncogene. 2006 Mar 13;25(11):1659-72
references.pmid: 16550166