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Antioxidant and hepatoprotective actions of the mold Monascus anka (also called Beni-Koji in Japan) against acetaminophen (AAP)-induced liver toxicity were investigated. Serum aspartate aminotransferase and glutathione S-transferase (GST) activities increased by AAP (180 mg/kg, i.p.) treatment were depressed when the Beni-Koji preparation (4 ml/kg, i.p.) was given 15 and 1 hr before AAP administration. The decrease in liver cytosolic GST activity by AAP, reflecting the release of the enzyme into serum, was also blocked by the mold. Cytochrome P450 activity was inhibited by the Beni-Koji preparation. These results suggest that M. anka prevents AAP-induced liver toxicity by both antioxidant action and the inhibition of AAP metabolism.

The antimetastatic effect of cepharanthin with or without 5-fluorouracil (5-FU) was examined in an experimental model of lung metastasis induced by Lewis lung carcinoma (3LL) in C57BL/6crSlc mice. Injection of cepharanthin i.p. after removal of the implanted primary tumor inhibited the development of lung metastases. Combination therapy with cepharanthin plus 5-FU inhibited significantly the lung metastases. Lung metastases were inhibited by i.v. injection of peritoneal macrophages activated with cepharanthin. Cepharanthin depressed aniline hydroxylase and aminopyrine demethylase activities of the hepatic microsomal drug-metabolizing system in tumor-bearing mice. Moreover, the concentration of 5-FU in the tissues (lung, liver, kidney, spleen and blood) was increased significantly by coadministration of cepharanthin. A possible mechanism of the inhibition of lung metastases by treatment with cepharanthin may be that this drug acts through macrophage activation and depression of the hepatic microsomal drug-metabolizing system. These findings raise the possibility that combination therapy with cepharanthin plus 5-FU may have clinical value in the prevention of cancer metastasis.

The effect of an acute or a successive administration of endotoxin (lipopolysaccharide obtained from Escherichia coli, LPS) on the hepatic drug-metabolizing system in vivo and in vitro was examined in mice. An acute LPS (5 mg/kg, i.v.) administration or a successive LPS (5-20 mg/kg, i.p., a day for 6 days) administration prolonged the duration of pentobarbital sleeping time and reduced the rate of hepatic microsomal metabolism of pentobarbital, aminopyrine, aniline and cyclophosphamide and reduced cytochrome P-450 content as compared with those in the control mice. No change of these parameters, however, was observed by an acute treatment with LPS to the successively LPS-treated mice. In addition, the LD50's of aminopyrine and pentobarbital and the ED50 of aminopyrine were reduced by an acute administration of LPS in control mice. No change of both parameters, however, was observed in the successively LPS-treated mice with or without an acute administration of LPS.

We have examined the effect of dietary protein deficiency on rat hepatic drug-metabolizing enzyme system for a period of two months. Cytochrome P-450 and b5 contents in liver microsomes, which were plotted on semilogarithmic paper as a function of the time of deficiency, showed biphasical reductions during protein deficiency: rapid decreases in the first 3 weeks were followed by more gradual decreases. However, the three enzymatic activities examined, i.e. aminopyrine demethylase, aniline hydroxylase and p-nitroanisole demethylase, were not reduced at a uniform rate. In the earlier phase, activities of the former two enzymes were reduced more rapidly than that of the last phase. This biphasical and non-uniform reduction of enzymatic activities suggests the existence of two or more cytochrome P-450 subspecies in non-depleted male rats. Intraperitoneal administration of well-known environmental pollutants, polychlorinated dibenzofurans and biphenyls (100 micrograms and 100 mg/kg, respectively) to the depleted rats resulted in a marked induction of drug-metabolizing enzymes. However, as the deficiency became more severe (2 months), the induction declined to a considerable degree, especially in the case of polychlorinated biphenyl administration.

The effects of acute (24-, 48- or 72-hr) water deprivation on the disposition kinetics of trimethadione (TMO) and its only metabolite, dimethadione (DMO), and on the microsomal hepatic drug-oxidizing enzyme activities were investigated in male rats. The DMO/TMO ratios in the serum at 2 hr after intravenous administration of 100 mg/kg TMO were significantly decreased in 48- and 72-hr water-deprived rats, but in 24-hr water-deprived rats, the DMO/TMO ratios were not changed as compared to controls and food restrictions. In the 48- and 72-hr water-deprived rats, contents of cytochrome p-450 and activities of aminopyrine N-demethylase were significantly decreased. On the other hand, activities of aniline hydroxylase in these rats were significantly increased as compared to controls and food restrictions. These results suggest that the effects of water deprivation on drug metabolism not only depend on the time of water deprivation but also vary with the indicator substrate.

The effect of "drugs for liver disease", protoporphyrin (PP) and phosphorylcholine (PC), on CCl4-induced liver injury was studied. Attention was given to the levels of microsomal drug-metabolizing enzyme and lipolytic enzyme activities and of some microsomal components such as phospholipid and peroxides. Administration of PP to CCl4-poisoned rats was found to increase the decreased microsomal drug-metabolizing enzyme activities, aminopyrine N-demethylase, aniline p-hydroxylase, cytochrome P-450 and b5 and lipolytic enzyme activity in CCl4-poisoned liver (12-20% increase as compared with those of the poisoned rats), and returned to control levels earlier than in CCl4-poisoned rats. Furthermore, administration of PP to CCl4-poisoned rats caused a decrease in the lipid peroxidation. A single dose of PP to normal rats was shown to increase these parameters, to a small extent. One of the mechanisms may be attributed to the fact that PP increases the biosynthesis of the hemoproteins by means of the incorporation of PP into the pigments and protects the membranes from lipid peroxides and the free radicals. On the other hand, administration of PC to the poisoned rats did not enhance the levels of the drug-metabolizing enzyme activities except for aminopyrine N-demethylase. Phospholipid phosphorous content, however, increased by 13-14% when PC was given. Thus, it is considered that PC may enhance the reconstitution of phospholipids in the injured membrane.

The glutathione S-transferase activity in liver and kidney cytosol was significantly decreased in short term diabetes induced with streptozotocin, whereas no decrease in the transferase was observed in phenobarbital-treated diabetic rats. Toxicity of chloroform was potentiated in streptozotocin- or phenobarbital-treated rats. The decrease in liver cytosolic and microsomal glutathione S-transferase activity was observed in long term diabetic rats, and only microsomal transferase activity was restored by insulin treatment. There was no release of glutathione S-transferases into the serum in the diabetic rats, and the transferases were not inhibited by streptozotocin in vitro. These results showed that glutathione S-transferase activity decreased during diabetes, and this decrease may contribute to altering drug metabolism and toxicity in diabetes.

Effects of benzphetamine, acetone, metyrapone and dimethylsulfoxide administration to rats on the metabolism of drugs by liver 9,000 x g supernatant fraction were studied herein. Activities for aniline hydroxylation and phenacetin O-deethylation were increased while ethylmorphine and benzphetamine N-demethylations were unchanged by the single administration of acetone, metyrapone or dimethylsulfoxide. Increase in aniline hydroxylase activity by about 53.4% and in phenacetin O-deethylase activity by about 44.4% were observed at 30 min after the single administration of benzphetamine whereas ethylmorphine N-demethylase activity was slightly decreased. NADPH-cytochrome P-450 reductase activity and cytochrome P-450 content were unaltered until 12 hr after the single administration of benzphetamine. Aniline hydroxylation was increased by the addition of benzphetamine to the incubation mixture and the increase in aniline hydroxylation caused by benzphetamine could be reversed by washing the microsomes.