Lack of correlation between lymphocytic mrna expression and activity of CYP3A4 and CYP2E1 In-vivo in alcoholics and non-alcoholics

Abstract

Lymphocyte mRNA levels may serve as a surrogate for activity of drug metabolizing enzymes. We conducted a study to examine the relationship between CYP2E1 and CYP3A4 lymphocyte mRNA levels and the clearances (CL) of oral chlorzoxazone (CHZ) and oral and IV midazolam (MDZ), respectively. 20 alcoholics (ALC) (> 140gm of alcohol/wk) and 20 non-alcoholics (N-ALC) (20 African-Americans 20 Caucasians) enrolled in the study. MDZ was given IV (0.05mg/kg over 30 min) and orally (5mg) on consecutive days. CHZ (500mg) was administered orally 8 hr after IV MDZ. mRNA was isolated from blood lymphocytes, CYP3A4 and 2E1 mRNA was quantitated using real time PCR. Serum CHZ and MDZ concentrations were determined by HPLC-UV or LC-MS. There was no significant difference (p>0.05) between ALC and N-ALC for CYP3A4 mRNA, MDZ CLORAL (149.4±87.8 vs 120.3±84.1 L/hr) and CLIV (36.9±12 vs 36.6±14.1 L/hr). No correlation was observed between lymphocytic CYP3A4 mRNA and CYP3A activity. CYP2E1 mRNA levels were not significantly different between ALC and N-ALC. In contrast, CHZ CLORAL was significantly greater (p<0.05) in ALC (31.5±11.9) compared to N-ALC (23.4±8.7) but no correlation was observed between CYP2E1 activity and mRNA. No significant race based differences were observed for either CYP mRNA or activity. In conclusion, lymphocyte CYP2E1 and CYP3A4 mRNA levels did not reflect hepatic CYP2E1 activity nor hepatic and intestinal CYP3A activity. Clinical Pharmacology & Therapeutics (2004) 75, P36–P36; doi: 10.1016/j.clpt.2003.11.137