Effect of ribavirin, levovirin and viramidine on liver toxicological gene expression in rats.
The ribavirin/interferon-alpha combination is currently the standard therapy for patients with chronic hepatitis C. However, ribavirin causes hemolytic anemia as a significant side-effect. Levovirin, an L-enantiomer of ribavirin, possesses similar immunomodulatory activity to ribavirin but lacks direct antiviral activity or hemolytic anemia. Viramidine is a liver-targeting prodrug of ribavirin with much less potential for hemolytic anemia. The aim of the present study is to profile the hepatic toxicological gene response to ribavirin, levovirin and viramidine. Rats were dosed orally with 120 mg kg(-1) day(-1) of ribavirin and viramidine and 2000 mg kg(-1) day(-1) of levovirin for 8 days. Ribavirin did not cause any significant change (>threefold) in gene expression as analyzed by the Affymetrix GeneChip technique. Levovirin decreased the mRNA level of CYP7A1 by fourfold but did not affect the expression of CYP27/CYP7B1 that functions as an alternative pathway for cholesterol metabolism. Viramidine down-regulated both expressed sequence tag 233569 and heat shock protein 86 genes threefold. The changes at mRNA level of these genes were confirmed by the reverse transcription competitive polymerase chain reaction technique. None of the compounds changed the liver/body weight ratio, the major cytochrome P-450 protein levels or enzyme activities. The data indicated that a high dose of ribavirin, levovirin or viramidine did not cause significant change at the transcription level of most of the liver toxicological genes.
Fang
Che
C
Research and Development, Ribapharm Inc, Costa Mesa, CA 92626, USA. cfang@ribapharm.com
Srivastava
Pramod
P
Lin
Chin-chung
CC
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D015870:Gene Expression; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity*; D013237:Stereoisomerism
D000998:Antiviral Agents; D012333:RNA, Messenger; D012254:Ribavirin; D003577:Cytochrome P-450 Enzyme System; C026956:taribavirin