Premium
Oral Contraceptives Worsen Endotoxin‐Induced Liver Injury in Rats
Author(s) -
Konno Akira,
Enomoto Nobuyuki,
Takei Yoshiyuki,
Hirose Miyoko,
Ikejima Kenichi,
Sato Nobuhiro
Publication year - 2002
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2002.tb02706.x
Subject(s) - liver injury , medicine , endocrinology , lipopolysaccharide , polymyxin b , pharmacology , chemistry , antibiotics , biochemistry
Background Oral contraceptives are widely used; however, these drugs occasionally cause liver injury. Recently, it was reported that estriol worsens alcoholic liver injury by the mechanism involving activation of Kupffer cells as a result of gut‐derived endotoxin. However, the relationship between oral contraceptives and endotoxin‐induced liver injury has not been elucidated. Here we show that oral contraceptives sensitize Kupffer cells via a mechanism dependent on increased gut permeability to endotoxin. Methods Female Wistar rats (200–250 g) were given intraperitoneally a combination of estradiol (35 ng/kg of 17α‐Ethynylestradiol) and progesterone (2 μg/kg of Norethindrone), each dose being similar to that contained in oral contraceptives (EP treatment). After 24 hr, a sublethal dose of lipopolysaccharide (LPS; 5 mg/kg) was injected via the tail vein. In some experiments, antibiotics (150 mg/kg/day of polymyxin B and 450 mg/kg/day of neomycin) were administered orally for 4 days before EP treatment. Gut permeability was measured in isolated segments of ileum by translocation of horseradish peroxidase. Kupffer cells were isolated and cultured in RPMI 1640 + 10% fetal bovine serum for 24 hr. After addition of LPS (100 ng/ml) to the culture medium, intracellular calcium concentration ([Ca 2+ ] i ) was measured with fura‐2. Results Liver histology in rats given EP treatment intraperitoneally followed by an injection of LPS (5 mg/kg) 24 hr later revealed pronounced liver damage with massive necrosis. Whereas mean values of alanine aminotransferase (ALT) in the control, nontreated rats were 30 ± 6 IU/liter, ALT increased to 75 ± 21 IU/liter 24 hr after LPS injection. This increase was aggravated 6‐fold (483 ± 118 IU/liter; p < 0.05) by EP treatment. The EP treatment‐induced increase in ALT was completely blocked by antibiotics (82 ± 26 IU/liter; p < 0.05). Gut permeability was increased approximately 10‐fold with EP treatment. This increase in gut permeability was not altered by treatment with nonabsorbable antibiotics. In isolated Kupffer cells, LPS increased [Ca 2+ ] i of Kupffer cells in control rats from basal levels (36 ± 8 nmol/liter) to 100 ± 8 nmol/liter. In contrast, the LPS‐induced [Ca 2+ ] i elevation was approximately 3‐fold greater in the group given EP treatment before 24 hr (305 ± 17 nmol/liter; p < 0.05). This increase was also blocked completely by treatment with antibiotics (128 ± 13 nmol/liter). Similar results were obtained for LPS‐induced tumor necrosis factor‐α production by Kupffer cells from either control or EP treatment group. The increased tumor necrosis factor‐α production as a result of EP treatment was blocked completely by antibiotics. Conclusions These results indicate that EP treatment in vivo sensitizes Kupffer cells to LPS via a mechanism dependent on the portal increase of gut‐derived endotoxin. This event suggests that oral contraceptives exacerbate alcoholic liver injury.