Generation and characterization of a serum albumin‐humanized mouse model for biomarker discovery

Abstract

The aim of this study is to develop a serum albumin‐humanized mouse model, for identifying human protein biomarkers of exposure to hazardous xenobiotics. The albumin‐humanized mouse was generated via cross‐breeding between a human albumin‐transgenic mouse and an albumin‐null mouse. The ability of human and mouse albumins to react with metabolites of the lung carcinogen 4‐(methylnitrosamino)‐l‐(3‐pyridyl)‐1‐butanone (NNK) was compared. Adult albumin‐humanized mice and wild‐type mice were treated with NNK (100 mg/kg body weight, IP). Blood, liver, and lung were analyzed 6 hours after NNK treatment. The NNK metabolite 4‐hydroxy‐l‐(3‐pyridyl)‐1‐butanone (HPB), free or as albumin‐HPB adduct, was detected in the plasma, whereas the O6‐methyl‐deoxyguanosine (O6‐mdG) DNA adduct, formed via NNK bioactivation, was detected in lung and liver. Results of quantitative analyses revealed lower levels of O6‐mdG in tissues of the humanized mice (10.4 and 85.5 pmol/μmol guanine, for lung and liver, respectively) than in wild‐type mice (18.4 and 240 pmol/μmol guanine, for lung and liver, respectively), a difference possibly explained by differing pharmacokinetic profiles of NNK. Interestingly, although a substantial genotype‐related difference was not observed in free HPB levels in the plasma (0.31 and 0.39 ng/ml, for wild‐type and humanized, respectively), human albumin‐HPB adduct levels in the humanized mouse were 6X higher than mouse albumin‐HPB adduct levels in the wild‐type mouse (per mg albumin). These data suggest that human and mouse albumins have different reactivities with reactive NNK metabolites and they illustrate the utility of the albumin‐humanized mouse model for biomarker discovery.Support or Funding InformationSupported in part by NIH grant CA092596