@article {Arora921, author = {Vikram Arora and Derek C. Knapp and Barbara L. Smith and Mary L. Statdfield and David A. Stein and Muralimohan T. Reddy and Dwight D. Weller and Patrick L. Iversen}, title = {c-Myc Antisense Limits Rat Liver Regeneration and Indicates Role for c-Myc in Regulating Cytochrome P-450 3A Activity }, volume = {292}, number = {3}, pages = {921--928}, year = {2000}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/292/3/921}, eprint = {https://jpet.aspetjournals.org/content/292/3/921.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }