The effects of dietary flaxseed on the Fischer 344 rat. III. Protection against CCl(4)-induced liver injury.

The hepatotoxic effect of carbon tetrachloride (CCl(4)) administered by gavage at 0.25 ml CCl(4) (1:1 in olive oil) per 100 g body weight was examined 24 h later in regular chow fed (RC) and 10% flax chow fed (FC) male and female Fischer 344 rats. CCl(4)-treated RC rats were subdued, lethargic and unkempt. CCl(4)-treated FC rats were much less affected. CCl(4) treatment resulted in loss of weight in RC and FC rats. In males, the weight loss was 6.7% body mass in RC rats compared to 5.6% body mass in FC rats. In females, the weight loss was 7.5% body mass in both RC and FC rats. While CCl(4) treatment increased the level of the liver injury marker plasma alanine aminotransferase (ALT) in RC rats, this CCl(4) effect was significantly attenuated in FC rats. In male rats, the ALT increase was 435-fold in RC rats and 119-fold in FC rats, over that of their respective controls. In female rats, the ALT increase was 454-fold in RC rats and 381-fold in FC rats, over that of their respective controls. These results provide evidence that flax consumption protects the liver against injury and that the extent of the protection is sex dependent. CCl(4) had no effect on the plasma level of gamma-glutamyltranspeptidase (gammaGT) in RC and FC rats supporting the contention that plasma gammaGT is not a useful marker for acute liver injury which is seen in this model. The activity of gammaGT was increased in the livers of FC rats compared to RC rats: 2.7-fold in males and 1.5-fold in females. In RC rats, the activity of liver gammaGT was decreased by CCl(4) treatment: 70% in the male and 25% in the female. However, this CCl(4) effect was reversed or abolished by flax consumption. Compared to RC rats: in male FC rats, CCl(4) actually increased the activity of liver gammaGT 1.28-fold; while in female FC rats, the depressing effect of CCl(4) treatment was abolished. The flax-induced preservation of gammaGT in the liver in response to injury may be involved in the observed hepatoprotection through generation of GSH. In RC male rats, CCl(4) treatment effected a 25% reduction in plasma glucose levels. There was no decrease in CCl(4)-treated FC male rats. In female rats, CCl(4) treatment effected a 21% decrease in plasma glucose levels in both RC and FC rats. In conclusion, multiple parameters for acute CCl(4)-induced injury were attenuated in the FC compared to the RC rat. That flaxseed consumption conferred greater protection against liver injury in the male than in the female suggests an involvement of the estrogenic lignan component of flaxseed. We discuss the possibility that this hepatoprotection is through a flax lignan-induced increase in reduced glutathione related to a flax effect on the activity of liver gammaGT in the resting state and the maintenance of its activity in response to injury.