TY - JOUR T1 - <strong>Inter-individual variability and differential tissue abundance of mitochondrial amidoxime reducing component (mARC) in humans</strong> JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.121.000805 SP - DMD-AR-2021-000805 AU - Deepak Ahire AU - Abdul Basit AU - Lisa J. Christopher AU - Ramaswamy Iyer AU - J. Steven Leeder AU - Bhagwat Prasad Y1 - 2021/01/01 UR - http://dmd.aspetjournals.org/content/early/2021/12/23/dmd.121.000805.abstract N2 - Mitochondrial amidoxime-reducing component (mARC) enzymes are molybdenum-containing proteins that metabolize a number of endobiotics and xenobiotics. The interindividual variability and differential tissue abundance of mARC1 and mARC2 were quantified using targeted proteomics in three types of tissue fractions: i) pediatric liver tissue homogenates, ii) total membrane fraction of the paired liver and kidney samples from pediatric and adult donors, and iii) pooled S9 fractions of the liver, intestine, kidney, lung, and heart. The absolute levels of mARC1 and mARC2 in the pediatric liver homogenate were 40.08 {plus minus} 4.26 and 24.58 {plus minus} 4.02 pmol/mg homogenate protein, respectively, and were independent of age and sex. In the total membrane fraction of the paired liver and kidney samples, the abundance of hepatic mARC1 and mARC2 was comparable, whereas mARC2 abundance in the kidney was ~9-fold higher in comparison to mARC1. The analysis of the third set of samples (i.e., S9 fraction) revealed that mARC1 abundance in the kidney, intestine, and lung was 5 to 13-fold lower than the liver S9 abundance, whereas mARC2 abundance was ~3- and 16-fold lower in the intestine and lung than the liver S9, respectively. In contrast, the kidney mARC2 abundance in the S9 fraction was ~2.5-fold higher as compared to the hepatic mARC2 abundance. The abundance of mARC enzymes in the heart was below the limit of quantification (~ 0.6 pmol/mg protein). The mARC enzyme abundance data presented here can be used to develop physiologically based pharmacokinetic models for the prediction of in vivo pharmacokinetics of mARC substrates. Significance Statement A precise targeted quantitative proteomics method was developed and applied to quantify newly discovered drug-metabolizing enzymes, mitochondrial amidoxime-reducing component (mARC) in pediatric and adult tissue samples. The data suggest that mARC enzymes are ubiquitously expressed in an isoform-specific manner in the human liver, kidney, intestine, and lung, and the enzyme abundance is not associated with age and sex. These data are important for developing physiologically based pharmacokinetic models for the prediction of in vivo pharmacokinetics of mARC substrates. ER -