RT Journal Article
SR Electronic
T1 c-<em>Myc</em> Antisense Limits Rat Liver Regeneration and Indicates Role for c-<em>Myc</em> in Regulating Cytochrome P-450 3A Activity
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 921
OP 928
VO 292
IS 3
A1 Vikram Arora
A1 Derek C. Knapp
A1 Barbara L. Smith
A1 Mary L. Statdfield
A1 David A. Stein
A1 Muralimohan T. Reddy
A1 Dwight D. Weller
A1 Patrick L. Iversen
YR 2000
UL http://jpet.aspetjournals.org/content/292/3/921.abstract
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