Decreased levels of S-adenosylmethionine (SAM) and hypomethylation of the H-ras gene in transformed pancreatic acinar cells from ddI-treated rats (Meeting abstract).

Important note: Information in this article was accurate in 1998. The state of the art may have changed since the publication date.

Decreased levels of S-adenosylmethionine (SAM) and hypomethylation of the H-ras gene in transformed pancreatic acinar cells from ddI-treated rats (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 38:A1198 1997. Unique Identifier : AIDSLINE ICDB/98638198
Lyn-Cook BD; Wise C; Green B; Johnson J; Jin B; Sandberg JA; Patterson TA; Slikker W; Divisions of Molecular Epidemiology and Neurotoxicology,; FDA/NCTR, Jefferson, Arkansas 72079

Abstract: Acute pancreatitis is often detected in AIDS patients given dideoxyinosine (ddI, Videx), a nucleoside analog. This study was undertaken to determine the molecular effects on normal pancreatic acinar cells in vivo and in vitro from controls and ddI-treated animals. Animals were dosed twice daily with 415 mg/kg ddI for 5, 10, 15, or 20 weeks. Animals dosed more than 10 wks showed decreased levels of SAM using HPLC analysis. Levels in pancreatic tissue after 10 wks were 6.41+/-0.55 for controls and 4.11+/-0.20 for ddI-treated animals. Pancreatic acinar cells isolated from controls and ddI-treated animals and subcultured for several passages revealed a remarkably decreased SAM level (ng of SAM/million cells, controls 34.94+/-5.9 and ddI, 14.02+/-2.34, p less than 0.001). S-adenosylmethionine: S-adenosylhomocysteine (SAM/SAH) ratios were 17.76+/-2.64 for control and 2.96+/-0.07 for ddI (p less than 0.0001). Cultured pancreatic acinar cells from ddI-treated rats demonstrated enhanced growth, activation and hypomethylation of the H-ras gene. These cells also displayed altered morphology. This study indicates that drugs such as ddI may exert their adverse effects through non-genotoxic mechanisms. Such changes in the overall methylation status could result in the activation of proto-oncogenes, such as ras, that are involved in the signal transduction pathway.

Keywords: Animal Cell Line, Transformed Cells, Cultured Didanosine/*PHARMACOLOGY *Genes, ras Methylation Pancreas/CYTOLOGY/*DRUG EFFECTS/METABOLISM Rats S-Adenosylmethionine/*METABOLISM Signal Transduction ABSTRACT
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M9820759

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