PT - JOURNAL ARTICLE AU - Arora, Vikram AU - Knapp, Derek C. AU - Smith, Barbara L. AU - Statdfield, Mary L. AU - Stein, David A. AU - Reddy, Muralimohan T. AU - Weller, Dwight D. AU - Iversen, Patrick L. TI - c-<em>Myc</em> Antisense Limits Rat Liver Regeneration and Indicates Role for c-<em>Myc</em> in Regulating Cytochrome P-450 3A Activity DP - 2000 Mar 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 921--928 VI - 292 IP - 3 4099 - http://jpet.aspetjournals.org/content/292/3/921.short 4100 - http://jpet.aspetjournals.org/content/292/3/921.full SO - J Pharmacol Exp Ther2000 Mar 01; 292 AB - Expression of c-myc protein is associated with cell proliferation. The present study uses antisense oligomers to inhibit c-mycexpression in the regenerating rat liver after 70% partial hepatectomy (PH). Antisense phosphorodiamidate morpholino oligomers (novel DNA analogs) were administered i.p. immediately after surgery to block expression of c-myc within the first 24 h after PH. A 20-mer PMO complimentary to the c-myc mRNA at the translation start site was an effective sequence (AVI-4126, 5′-ACGTTGAGGGGCATCGTCGC-3′). A single i.p. dose of 0.5 mg/kg AVI-4126 caused reduction of the regenerating liver c-myc protein in a sequence-specific and dose-dependent manner. Inhibition of c-myc expression resulted in reduction of proliferating cell nuclear antigen and arrested cells in the G0/G1 phase of the cell cycle. The ratio of G2:G0 cell populations in the regenerating liver 24 h after PH dropped from 29.1 in saline vehicle-treated rats to 18.0 in rats treated with 2.5 mg/kg AVI-4126. The expression of cell cycle checkpoint protein p53 was inhibited with increasing doses of AVI-4126, but expression of p21waf-1 was unaffected. The activity of cytochrome P-450 3A2 (CYP3A2) was evaluated by immunoblot analysis and erythromycin N-demethylation. AVI-4126 did not alter CYP3A activity in nonhepatectamized animals but showed a dose-dependent decrease in PH rats. We conclude that AVI-4126, antisense oligomer to c-myc, can reduce cell proliferation in the regenerating rat liver. Furthermore, inhibition of c-myc may indirectly influence the expression of CYP3A. The American Society for Pharmacology and Experimental Therapeutics