title: Low membrane protein sulfhydrils but not G6PD deficiency predict ribavirin-induced hemolysis in hepatitis C.
abstract: Hemolysis is a frequent adverse effect of ribavirin (RBV). It has been suggested that oxidative stress plays a role, but mechanisms and predictive risk factors for severe forms remain unknown. Markers of redox status were determined in erythrocytes of 34 patients with hepatitis C-four of them with glucose-6-phosphate-dehydrogenase (G6PD) deficiency-before and during treatment with RBV and interferon (IFN) and were compared with 10 healthy control subjects. In addition, erythrocytes were incubated with RBV, and the effects of dipyridamole (DPD), diethylmaleate (DEM), and glutathione ester (GSHE) were studied in vitro. Of the 30 patients without G6PD deficiency who were treated with RBV and IFN-alpha, five developed major hemolysis (Delta hemoglobin > 6 g/dL) and 25 developed minor hemolysis (Delta hemoglobin < 2.5 g/dL). Patients with major hemolysis had lower median pretreatment values of membrane protein sulfhydrils than patients with minor hemolysis (28.4 vs. 36.7 nmol/mg, P <.001). Erythrocytes of G6PD-deficient patients were not more susceptible to RBV-induced hemolysis. In in vitro incubations of erythrocytes, DEM enhanced the RBV-induced decrease of glutathione, protein sulfhydrils, and osmotic resistance. Supplementation of GSHE and DPD prevented the RBV-induced decrease in osmotic resistance, adenosyl triphosphate (ATP), and 2,3-diphosphoglycerate (DPG), the loss of glutathione and protein sulfhydrils, and the formation of thiobarbituric acid reactive substances (TBARs). In conclusion, the data indicate that low membrane protein sulfhydrils prior to therapy but not G6PD deficiency are predictive of RBV-induced major hemolysis. In vitro, GSHE and DPD reduce the RBV-associated oxidative stress in erythrocytes and prevent the increase in osmotic fragility, suggesting that these compounds might decrease the risk of hemolysis in patients.
authors.affiliation: Section of Internal Medicine, Department of Internal Medicine and Public Medicine, University of Bari, Bari, Italy.
authors.forename: Ignazio
authors.initials: I
authors.lastname: Grattagliano
authors.forename: Stefan
authors.initials: S
authors.lastname: Russmann
authors.forename: Vincenzo O
authors.initials: VO
authors.lastname: Palmieri
authors.forename: Peter
authors.initials: P
authors.lastname: Jüni
authors.forename: Florian
authors.initials: F
authors.lastname: Bihl
authors.forename: Piero
authors.initials: P
authors.lastname: Portincasa
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palasciano
authors.forename: Bernhard H
authors.initials: BH
authors.lastname: Lauterburg
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002462:Cell Membrane / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D019803:Glutathione Disulfide / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000150:complications / Q000378:metabolism*; D006461:Hemolysis / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008298:Maleates / Q000494:pharmacology; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects*; D013438:Sulfhydryl Compounds / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D008298:Maleates; D013438:Sulfhydryl Compounds; D012254:Ribavirin; D004176:Dipyridamole; C014476:diethyl maleate; D005978:Glutathione; D019803:Glutathione Disulfide