A pilot study of leukocyte expression patterns for drug metabolizing enzyme and transporter transcripts in autoimmune glomerulonephritis

作者：Joy Melanie S^*; Roberts Brittney V; Wang Jinzhao; Hu Yichun; Hogan Susan L; Falk Ronald J

来源：International Journal of Clinical Pharmacology and Therapeutics, 2014, 52(4): 303-313.

DOI：10.5414/CP201972

• glomerulonephritis
• drug metabolizing enzymes
• transporters
• uridine glucuronosyl
• transferases (UGTs)
• cytochrome P450 2B9
• ABCB1
• ABCC2
• ABCG2

Objective: Leukocyte mRNA expression patterns of drug metabolizing enzyme genes and transporter genes that are relevant for the disposition of cyclophosphamide and mycophenolate were studied. The relationships between expression and patient-level data and pharmacokinetics were evaluated. Methods: The study included patients with glomerulonephritis secondary to lupus nephritis (SLE, n = 36), small vessel vasculitis (SVV, n = 35), healthy controls (HC, n = 10), and disease controls (VC, n = 5; LC, n = 5). Transcript assays targeted metabolizing enzymes (UGT1A7, UGT1A9, UGT2B7, CYP3A4, CYP2C9, CYP2B6) and transporters (ABCB1, ABCC2, ABCG2, SLCO1A2). Genotyping for specific variants was conducted. Group transcript fold-changes were evaluated. Patient level data was evaluated for transcript foldchange and disease, treatment, gender, race, and genotype. Results: Significant differences were noted in expression of UGT1A7, ABCB1, and ABCC2; for UGT1A7, SVV (0.17 +/- 0.42; p < 0.05) and SLE (0.03 +/- 0.1; p < 0.05) groups had lower expression than HC (0.79 +/- 2.02). For ABCB1, SLE had a lower expression (0.33 +/- 0.21; p < 0.05) than HCs (1 +/- 0.82). For ABCG2, SVV group had a lower expression (0.17 +/- 0.14; p < 0.05) than HCs (1 +/- 1.82). Differences in expression of ABCC2 approached statistical significance with VC patients (2.02 +/- 1.13) exhibiting higher expression than SVV patients (1.06 +/- 1.11; p = 0.05). The relationships between transcript expression and patient-level data demonstrated; ABCC2 expression was different by race (1.26 +/- 1.82 Caucasian versus 1.37 +/- 0.86 non-Caucasian; p = 0.049) and CYP2B6 expression was different by treatment (2.07 +/- 2.94 cyclophosphamide versus 0.45 +/- 0.5 mycophenolate; p = 0.01). Conclusions: The current study showed differential expression of drug metabolizing enzyme and transporter transcripts and contributes to the literature on transcript expression of drug transporters in leukocytes. The implications of altered local metabolism and transport in leukocytes may be important in autoimmune diseases and transplant patients where treatment is targeted to leukocytes.

• 出版日期2014-4