Hepatic Microsomal Mixed-function Oxidase Activities Research Articles

The effects of nitrofuran derivatives on hepatic microsomal mixed-function oxidase activity in rats

The effects of four nitrofuran antibacterial food additives and animal drugs were studied on the mixed-function oxidase activity in rat hepatic microsomes. Dietary administration (0.03 to 0.3%) of the compounds for 7 days to Wistar male rats, produced varying degrees of liver enlargement and some compounds exhibited a reducing effect on cytochrome P -450 concentrations and NADPH-cytochrome c reductase activity in hepatic microsomes. The activity of aminopyrine N -demethylase and aniline hydroxylase was affected in varying ways by these compounds. Among these, 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide(furylfuramide) was most potent in increasing the liver weight and in reducing the activity of these microsomal enzymes. In male rats fed a 0.1% furylfuramide-containing diet, the cytochrome P -450 concentration and the activity of aminopyrine N -demethylase and aniline hydroxylase were markedly reduced throughout the experimental period up to 29 days, while cytochrome b 5 and the activity of NADPH-cytochrome c reductase were not changed so markedly. Similar results were also obtained in female rats fed the furylfuramide diet for 3 days, but the reduction in enzyme activities was smaller than that in male rats. Dietary administration of furylfuramide for 3 days to phenobarbital- or 3-methylcholanthrene-pretreated female rats resulted in a marked decrease in the activity of the microsomal enzymes. The pentobarbital sleeping time was prolonged by 57% in male rats fed a 0.1% furylfuramide diet for 7 days. The incubation in vitro of furylfuramide (0.05 m m ) with microsomes from livers of nontreated male rats resulted in decreased activity of aminopyrine N -demethylase and aniline hydroxylase.

Enhancement of hepatic microsomal drug metabolism in vitro following ethanol administration.

1. Administration of ethanol intraperitoneally at low dosages (10-25 mg/kg) to rats stimulates hepatic microsomal mixed-function oxidase activity in vitro. 2. Pretreatment with ethanol administered orally has no effect on in vivo drug metabolism as measured by pentobarbitone plasma half-life and has no effect on the excretion of ascorbic acid. Ethanol administration does not enhance its own binding to cytochrome P-450. 3. These observations suggest that the administration of ethanol, at moderate dosage, does not give rise to induction of hepatic cytochrome P-450. 4. Unwashed hepatic microsomes are contaminated with alcohol dehydrogenase, but pretreatment with ethanol does not increase microsomal generation of NADH. 5. Pretreatment with ethanol has no stimulatory effect on NADH-NADP+ transhydrogenation. 6. The stimulation of hepatic drug metabolism in vitro following administration of ethanol is not due to increased cytochrome P-450 nor to increased NADPH, per se, but appears to result from an increase in the activity of NADPH-cytochrome c reductase.

Response of hepatic microsomal mixed-function oxidases to various types of insecticide chemical synergists administered to mice

For several hours after a single intraperitoneal (i.p.) dose to mice, piperonyl butoxide, 2-methylpropyl 2-propynyl phenylphosphonate (NIA 16824), and 5,6-dichloro-l, 2,3-benzothiadiazole (WL 19255) inhibit hepatic microsomal mixed-function oxidase (mfo) activity and the apparent level of cytochrome P-450 but, after 24–72 hr, they induce increased mfo activity and P-450 content. Other types of insecticide chemical synergists studied are generally less active or inactive in this respect. The active compounds enhance the toxicity of several insecticide chemicals and markedly prolong hexobarbital sleeping time but not hexobarbital toxicity. The action of WL 19255 differs from that of piperonyl butoxide and NIA 16824 in that it is relatively non-specific in inhibiting enzymatic activity on several substrates, gives a more prolonged effect on P-450, and the magnitude of induction is greater.