Development of selective adsorbent for free-hemoglobin.

It is well-known that acute renal failure is often caused by hemolysis. Its possible causes may be free-hemoglobin (F-Hb), stroma freed from destroyed red blood cell, and their combined action. Especially, a great amount of F-Hb is liable to flow out during extracorporeal circulation. The plasma fractionation using a membrane has so far been applied to remove F-Hb (1). The molecular weight of F-Hb of 68,000 which is nearly equal to that of albumin has made it still difficult to separate F-Hb effectively. Recently, we have developed an adsorbent that is capable of selectively removing F-Hb and succeeded in obtaining its high adsorption performance.

Decreased induction of gamma-glutamyltransferase activity by 3'-methyl-4-dimethylaminoazobenzene in the liver of rats given carcinogen-containing diet for several generations.

gamma-Glutamyltransferase (G-GT) has been widely used as a marker of the preneoplastic stage of chemical carcinogenesis. We obtained male rats of Donryu strain that showed a reduced response to 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB) in terms of induction of G-GT activity in the liver, by giving rats of this strain diet containing the carcinogen for several generations. In these animals, hepatic G-GT activity was only slightly higher than normal even after more than 20 weeks of continuous post-weaning exposure to the carcinogen, and it decreased to below the normal level if administration of the carcinogen was discontinued. In normal male rats, administration of diet containing 3'-MeDAB for more than 2 weeks resulted in an increase in hepatic G-GT activity, and the activity was increased further by a single injection of hydrocortisone. This response to glucocorticoid was also lost in "3'-MeDAB-resistant rats." Transient elevation of fetal hepatic G-GT activity occurred at the end of gestation of "resistant rats" as well as normal rats, but the highest activity at birth of the "resistant rats" was significantly lower than that of normal rats. We observed retardation of tumor development in the liver of fourth and fifth generation rats maintained continuously on diet containing 3'-MeDAB.

Comparison of drug-metabolizing activities in the livers of carcinogen-sensitive parent rats and carcinogen-resistant descendants.

Donryu strain albino rats were maintained on a diet containing 0.06% 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) for nine successive generations. Some rats in the fourth to eighth generations showed marked resistance to the carcinogenic action of 3'-Me-DAB. In the liver where we found tumors, their size and number are smaller than in the corresponding original strain of rats fed on a diet containing 3'-Me-DAB. No significant differences were found in the total cytochrome P-450 contents or epoxide hydrolase activities of the livers of the resistant variant and the original strain, but the benzo(a)pyrene hydroxylase activity which is mainly attributed to cytochrome P-448 and glutathione S-transferase activity of the resistant variant were lower. The inductions of hepatic cytochrome P-488 and benzo(a)pyrene hydroxylase on administration of polychlorinated biphenyls or 3-methylcholanthrene were also lower in the resistant rats. In the mutagenicity test on Salmonella typhimurium TA 98 the liver 9000 X g supernatant fraction from 3'-Me-DAB-resistant F7 rats did not fully induce the mutagenicities of 3'-Me-DAB and several other carcinogens. Thus the resistance of F7 rats to the chemical carcinogen may be related to the lower activities of some drug-metabolizing enzymes and the poor inducibility of cytochrome P-448 in their liver, although selection of resistant rats should be continued for further generations before coming to a definite conclusion on biochemical basis of apparent resistance to 3'-Me-DAB.