EFFECT OF AFLATOXIN B1 ON NET SYNTHESIS OF ALBUMIN FIBRINOGEN AND ALPHA1-ACID GLYCOPROTEIN BY ISOLATED PERFUSED RAT LIVER

The isolated perfused rat liver has been used to study the influence of aflatoxin B1 on net synthesis of the plasma proteins albumin, fibrinogen, α1-acid glycoprotein and α2-(acute phase) globulin. Aflatoxin B1 was used because it may inhibit messenger RNA synthesis from DNA in a manner similar to that generally accepted for actinomycin D, thereby allowing estimates of half-lives of individual species of messenger RNA to be made by observation of changes in the rate of synthesis of individual proteins after administration of the drug. Livers of adult male Sprague-Dawley rats were perfused for 12 hr with defibrinated rabbit blood with l-lysine-1-14C and 500 mg glucose continually infused. Net changes in the specific plasma proteins were measured serologically. Aflatoxin B1 was added to the perfusate (half the total dose at the outset and the other half infused); although a dose of 62.5 μg aflatoxin B1 did not affect the net synthesis of albumin, fibrinogen, α1-acid glycoprotein or α2-(acute phase) globulin, doses of 125, 250, 500 or 1000 μg were associated with increasingly severe inhibition of synthesis manifest after 2-4 hr of perfusion. These data are consistent with short half-lives for messenger RNA for these plasma proteins; however, histological evidence of progressively more widespread parenchymal cell degeneration, necrosis and interstitial hemorrhage associated with doses of aflatoxin B1 above 62.5 μg strongly suggests that the impaired protein synthesis may in part have been secondary to cytotoxic effects. l-Lysme-1-14C incorporation into hepatic protein was inhibited progressively by increasing doses of aflatoxin B1. Significant elevations in rate of 14CO2 production from l-lysine-1-14C, in urea synthesis and in α-amino acid nitrogen accumulation were observed in perfusions with more than 125 μg aflatoxin B1. © 1969.