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Normalized testosterone glucuronide (TG/AG) as a potential urinary biomarker for highly variable UGT2B17 in children 7 to 18 years.

Abstract

UDP-glucuronosyltransferase 2B17 (UGT2B17) is a highly variable androgen- and drug-metabolizing enzyme. UGT2B17 exhibits a unique ontogeny profile characterized by a dramatic increase in hepatic protein expression from pre-pubertal age to adulthood. Age, sex, copy number variation (CNV), and single nucleotide polymorphisms only explain 26% of variability in protein expression, highlighting the need for a phenotypic biomarker for predicting inter-individual variability in glucuronidation of UGT2B17 substrates. Here we propose testosterone glucuronide (TG) normalized by androsterone glucuronide (TG/AG) as a urinary UGT2B17 biomarker, and examine the associations between urinary TG/AG and age, sex, and CNV. We performed targeted metabolomics of 12 androgen conjugates with LC-MS/MS in 63 pediatric subjects ages 7 to 18 years followed over 7 visits in 3 years. Consistent with the reported developmental trajectory of UGT2B17 protein expression, urinary TG/AG is significantly associated with age, sex, and CNV. In conclusion, TG/AG shows promise as a phenotypic urinary UGT2B17 biomarker.

Authors+Show Affiliations

Department of Pharmaceutics, University of Washington, Seattle, WA, USA, 98195.Department of Pharmaceutics, University of Washington, Seattle, WA, USA, 98195. Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, USA, 99202.Department of Pharmaceutics, University of Washington, Seattle, WA, USA, 98195.Department of Pharmaceutics, University of Washington, Seattle, WA, USA, 98195.Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Kansas City and University of Missouri-Kansas City, Kansas City, Missouri, USA.Department of Pharmaceutics, University of Washington, Seattle, WA, USA, 98195.Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Kansas City and University of Missouri-Kansas City, Kansas City, Missouri, USA.Department of Pharmaceutics, University of Washington, Seattle, WA, USA, 98195. Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, USA, 99202.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31900930

Citation

Zhang, Haeyoung, et al. "Normalized Testosterone Glucuronide (TG/AG) as a Potential Urinary Biomarker for Highly Variable UGT2B17 in Children 7 to 18 Years." Clinical Pharmacology and Therapeutics, 2020.
Zhang H, Basit A, Wolford C, et al. Normalized testosterone glucuronide (TG/AG) as a potential urinary biomarker for highly variable UGT2B17 in children 7 to 18 years. Clin Pharmacol Ther. 2020.
Zhang, H., Basit, A., Wolford, C., Chen, K. F., Gaedigk, A., Lin, Y. S., ... Prasad, B. (2020). Normalized testosterone glucuronide (TG/AG) as a potential urinary biomarker for highly variable UGT2B17 in children 7 to 18 years. Clinical Pharmacology and Therapeutics, doi:10.1002/cpt.1764.
Zhang H, et al. Normalized Testosterone Glucuronide (TG/AG) as a Potential Urinary Biomarker for Highly Variable UGT2B17 in Children 7 to 18 Years. Clin Pharmacol Ther. 2020 Jan 3; PubMed PMID: 31900930.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Normalized testosterone glucuronide (TG/AG) as a potential urinary biomarker for highly variable UGT2B17 in children 7 to 18 years. AU - Zhang,Haeyoung, AU - Basit,Abdul, AU - Wolford,Chris, AU - Chen,Kuan-Fu, AU - Gaedigk,Andrea, AU - Lin,Yvonne S, AU - Leeder,J Steven, AU - Prasad,Bhagwat, Y1 - 2020/01/03/ PY - 2020/1/5/entrez KW - UGT2B17 KW - biomarker KW - copy number variation KW - interindividual variability KW - ontogeny KW - testosterone glucuronide JF - Clinical pharmacology and therapeutics JO - Clin. Pharmacol. Ther. N2 - UDP-glucuronosyltransferase 2B17 (UGT2B17) is a highly variable androgen- and drug-metabolizing enzyme. UGT2B17 exhibits a unique ontogeny profile characterized by a dramatic increase in hepatic protein expression from pre-pubertal age to adulthood. Age, sex, copy number variation (CNV), and single nucleotide polymorphisms only explain 26% of variability in protein expression, highlighting the need for a phenotypic biomarker for predicting inter-individual variability in glucuronidation of UGT2B17 substrates. Here we propose testosterone glucuronide (TG) normalized by androsterone glucuronide (TG/AG) as a urinary UGT2B17 biomarker, and examine the associations between urinary TG/AG and age, sex, and CNV. We performed targeted metabolomics of 12 androgen conjugates with LC-MS/MS in 63 pediatric subjects ages 7 to 18 years followed over 7 visits in 3 years. Consistent with the reported developmental trajectory of UGT2B17 protein expression, urinary TG/AG is significantly associated with age, sex, and CNV. In conclusion, TG/AG shows promise as a phenotypic urinary UGT2B17 biomarker. SN - 1532-6535 UR - https://www.unboundmedicine.com/medline/citation/31900930/Normalized_testosterone_glucuronide_(TG/AG)_as_a_potential_urinary_biomarker_for_highly_variable_UGT2B17_in_children_7_to_18_years L2 - https://doi.org/10.1002/cpt.1764 DB - PRIME DP - Unbound Medicine ER -