[영문]Tetracycline in large doses induced a fatty liver in experimental animals(Zussman, 1968) and has been incriminated as a cause of fatty liver and hepatic dysfunction in man(Whalley et al., 1964).
Although the pathogenesis of tetracycline induced fatty liver is uncertain, one suggested mechanism has been that the tetracycline in high concentrations interfered with hepatic adenosine-triphosphate synthesis, resulting in impaired fat
metabolism(Wruble et al., 1965).
In as much as tetracycline inhibited protein synthesis in vitro(Feingold, 1963) and in vivo(Nikolov et al., 1961), and triglycerides were normally bound to hepatic lipid acceptor protein and were transported from liver to blood plasma as low
density beta lipoprotein, it seemed possible that tetracycline, in high concentrations, might inhibit hepatic lipid acceptor protein synthesis and thus impair the normal removal of triglycerides from the liver(Hansen et al., 1968).
Steiner et al.(1965) have speculated that the fatty change induced by tetracycline might result from adenosine-triphosphate and protein synthesis inhibition.
Furthermore, since the sexual difference of tetracycline toxicity was known and majority of reported cases of tetracycline toxicity have been obstetric, it might reasonable be asked if sex hormones and pregnancy predisposed to the development of fatty liver.
The present study assessed the roles of sex hormones and pregnancy in the pathogenesis of tetracycline induced fatty liver gy light and electron microscopic studies.
Materials and Methods
Male and female albino rats weighing around 200gm. were used for experiment and divided into the following groups:
1) Normal control,
a) Saline treated
b) Estrogen and progesterone treated
2) Tetracycline treated group
a) Tetracycline only treated
b) Tetracycline, estrogen and progesterone combined treated
c) Tetracycline treated during pregnancy.
The saline was injected intraperitoneally in a dose of 1.0ml. per day, and estrogen intramuscularly in a dose of 10,000 I.U. per day and progesterone 25mg. per day.
The chlortetracycline was injected intraperitoneally in a dose of 10mg. per day.
Two male and two female rats from each control group except the pregnant controls were killed after 1, 5 and 10 days, and two pregnant control rats at 1, 5, 10, 15 and 20 days.
Two male and two female rats from each experimental group except group of tetracycline treated during pregnancy rats were killed at 1, 2, 3, 5, 7 and 10 days. the group of tetracycline treated during pregnancy rats were divided into early and late pregnancy, and two female rats of each subgroup were killed at 1, 2,3, 5, 7 and 10 days respectively.
Over-all histologic alterations of the liver, kidneys and pancreas were observed by the routine hematoxyline-eosin staining technic.
The degree and the pattern of fatty changes were determined by the Oil red O staining, ribonucleic acid alterations by the methyl green pyronin staining and glycogen accumulation by PAS staining.
For the electron microscopic examinations, the liver tissue was fixed in 1% osmium tetraoxide and dehydrated with graded alcohol. The sections were cut with a glass knife following Epon 812 embedding in 400 to 500A thickness and stained with uranyl acetate and lead hydroxide.
Observation was made with the Hitachi 11-E model electron microscope.
Results and Discussion
The administration of tetracycline to rats resulted in a slight decreased in body weight, whereas the liver weight significantly increased in the animals receiving tetracycline, especially in the female rats. Histological examination of the rats receiving tetracycline revealed fatty change without evidence of inflammation or hepatic cell necrosis.
Generally the fatty change was more severe in tetracycline treated female rats compared with male rats.
The accumulation of the lipid started from the centrilobular area and spread to the periportal are in the animals treated with tetracycline.
The maximal intensity of fatty change in the liver was observed in the tetracycline treated during late pregnancy group, followed by the group of combined tetracycline, estrogen and progesterone treated female rats.
The ribonucleic acid of the cytoplasm and nucleoli of the hepatic cell and also the glycogen content decreased markedly in the tetracycline treated groups.
The electron microscopic examinations revealed marked dilatation of the rough endoplasmic reticulum with detachmen of ribosome, decrease of free ribosome, and mild swelling of mitochondria, these were noted in animals of the tetracycline
treated groups, except the tetracycline treated during late pregnancy group, which revealed marked mitochondrial swelling and cristae loss. The fatg lobules first appeared in the dilated endoplasmic reticulum as nemerous small electron dense granules, so called liposomes, in all tetracycline treated groups.
The present study assessed the roles of sex hormones and pregnancy in the pathogenesis of tetracycline induced fatty liver. The fatty change was severer in tetracycline treated late pregnancy rats and combined tetracycline, estrogen and progesterone treated rats compared with the nonpregnant and tetracycline only treated group, indicating that there existed a sexual and gestational difference in the reaction to tetracycline.
The accumulation of the fat in the liver cells started within the rough endophsmic reticulum, and was associated with histological and ultrastructural alterations suggestive of inhibition of protein synthesis in animals treated with tetracycline. The mechanism, possibly due to impaired synthesis of hepatic lipid acceptor protein, appeared to be the major cause of tetracycline induced fatty liver.
In addition to protein synthesis inhibition, mitochondrial changes were observed in the tetracycline treated during late pregnancy rats, which suggested that protein and adenosine triphosphate synthesis inhibition appeared to be the mechanism involved.