Universal Accessible Biomarkers of Drug-Induced Tissue Injury and Systemic Inflammation in Rat: Performance Assessment of TIMP-1, A2M, AGP, NGAL, and Albumin

• Published in: Toxicological sciences Vol. 187; no. 2; pp. 219 - 233
• Main Authors: Vlasakova, Katerina, Bourque, Jennifer, Bailey, Wendy J, Patel, Shetal, Besteman, Elizabeth G, Gonzalez, Raymond J, Sistare, Frank D, Glaab, Warren E
• Format: Journal Article
• Language: English
• Published: United States 26.05.2022
• Subjects: Acute Kidney Injury; Albumins; Animals; Biomarkers; Female; Inflammation; Lipocalin-2; Pregnancy; Pregnancy-Associated alpha 2-Macroglobulins; Rats; ROC Curve; Tissue Inhibitor of Metalloproteinase-1; α1-acid glycoprotein; α2-macroglobulin; rat; neutrophil gelatinase-associated lipocalin; tissue inhibitor of metalloproteinases; albumin; drug-induced tissue injury
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfac030

The ability to monitor for general drug-induced tissue injury (DITI) or systemic inflammation in any tissue using blood-based accessible biomarkers would provide a valuable tool in early exploratory animal studies to understand potential drug liabilities. Here we describe the evaluation of 4 biomarkers of tissue remodeling and inflammation (α2-macroglobulin [A2M], α1-acid glycoprotein [AGP], neutrophil gelatinase-associated lipocalin [NGAL], and tissue inhibitor of metalloproteinases [TIMP-1]) as well as the traditional serum parameter albumin as potential blood-based biomarkers of DITI and systemic inflammatory response (SIR). Biomarker performance was assessed in 51 short-term rat in vivo studies with various end-organ toxicities or SIR and receiver operating characteristic curves were generated to compare relative performances. All 4 biomarkers performed well in their ability to detect DITI and SIR with an area under the curve (AUC) of 0.82-0.78, however TIMP-1 achieved the best sensitivity (at 95% specificity) of 61%; AGP, NGAL, and A2M sensitivity was 51%-52%. AUC for albumin was 0.72 with sensitivity of 39%. A2M was the best performer in studies with only SIR (AUC 0.91). In the subset of studies with drug-induced vascular injury, TIMP-1 performed best with an AUC of 0.96. Poor performance of all tested biomarkers was observed in samples with CNS toxicity. In summary, TIMP-1, A2M, AGP, and NGAL demonstrated performance as sensitive accessible biomarkers of DITI and SIR, supporting their potential application as universal accessible tissue toxicity biomarkers to quickly identify dose levels associated with drug-induced injury in early exploratory rat safety and other studies.