title: Immunomodulatory effects by oral contraceptives in normal and cholestatic female rats: role of cytokines.
abstract: Oral contraceptives (OC) may cause intrahepatic cholestasis or increase a pre-established liver damage. OC effects on hepatic injury biochemical markers remain contradictory and the role of cytokines in those processes is fairly unknown. Two doses, simple or double, of the OC combination ethinylestradiol/norgestrel were administered during 14 or 28 days to normal and cholestatic female rats. Liver damage markers and the cytokines tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) were determined in plasma and liver. OC caused ambiguous results on cholestasis indicators, even more in cholestatic rats. Necrosis rose during cholestasis while OC lowered it in normal rats. Fibrosis was induced by cholestasis but OC double dose or intake time diminished that. Cholestasis depleted glycogen while OC did not alter it. Double dose or time of administration of OC significantly elevated the lipid peroxidation. Cholestasis modified plasma and liver cytokines but OC remarkably altered them in normal and cholestatic animals. TNF-α as well as IL-10 were increased in both tissues by OC, such rise was higher in normal rats. TGF-β was augmented by OC and more in cholestatic rats receiving double dose. Thus, OC modified most liver injury markers in normal rats although more pronouncedly in cholestatic ones, as well as increased hepatic oxidative stress. Liver fibrosis was decreased and corroborated by histological analysis even when TGF-β is elevated by OC. OC strongly immunomodulate cytokines that mediate liver damage or worsen a prior hepatopathy; those processes are influenced by dose, administration time and OC formulation.
authors.affiliation: Centro de Investigación en Biología de la Reproducción, Medicina-I.C.Sa. Universidad Autónoma del Estado de Hidalgo, Hidalgo, Mexico. Electronic address: efernan@uaeh.edu.mx.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fernández-Martínez
authors.affiliation: Centro de Investigación en Biología de la Reproducción, Medicina-I.C.Sa. Universidad Autónoma del Estado de Hidalgo, Hidalgo, Mexico.
authors.forename: Elvia
authors.initials: E
authors.lastname: Pérez-Soto
authors.affiliation: Centro de Investigación en Biología de la Reproducción, Medicina-I.C.Sa. Universidad Autónoma del Estado de Hidalgo, Hidalgo, Mexico.
authors.forename: Carlos
authors.initials: C
authors.lastname: González-Hernández
authors.affiliation: Centro de Investigación en Biología de la Reproducción, Medicina-I.C.Sa. Universidad Autónoma del Estado de Hidalgo, Hidalgo, Mexico.
authors.forename: Mario I
authors.initials: MI
authors.lastname: Ortiz
authors.affiliation: Departamento de Farmacología, Cinvestav-I.P.N., Apdo. Postal 14-740, D.F., Mexico.
authors.forename: Víctor
authors.initials: V
authors.lastname: Pérez-Álvarez
authors.affiliation: Departamento de Farmacología, Cinvestav-I.P.N., Apdo. Postal 14-740, D.F., Mexico.
authors.forename: Pablo
authors.initials: P
authors.lastname: Muriel
authors.affiliation: Departamento de Infectómica y Patogénesis Molecular, Cinvestav-I.P.N., Apdo. Postal 14-740, D.F., Mexico.
authors.forename: Mineko
authors.initials: M
authors.lastname: Shibayama
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002779:Cholestasis / Q000188:drug therapy* / Q000473:pathology; D003276:Contraceptives, Oral / Q000008:administration & dosage* / Q000009:adverse effects; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D019304:Ethinyl Estradiol-Norgestrel Combination / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D056747:Immunomodulation; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015415:Biomarkers; D003276:Contraceptives, Oral; D016207:Cytokines; D019304:Ethinyl Estradiol-Norgestrel Combination
keywords: Cholestasis; Cytokines; Fibrosis; Immunomodulation; Liver; Oral contraceptives