rifampin and cobaltous-chloride

We examined the paraquat detoxicative system in mouse livers. The survival rate of mice receiving 50 mg/kg paraquat was 41% at 7 days and significantly rose to 88, 64, 69% with pretreatment with phenytoin, phenobarbital, and rifampicin, respectively. Phenytoin induced activity in NADPH-cytochrome P450 reductase, CYP3A, CYP2B, and CYP2C that was 3 to 4 times higher than that of the controls. Phenobarbital induced CYP2B and rifampicin induced CYP3A, respectively, in addition to NADPH-cytochrome P450 reductase. 3-Methylcholanthrene did not induce these enzymes and did not alter the survival rate. All the mice pretreated with CoCl(2) (a CYP synthesis inhibitor) or SKF 525-A (a CYP inhibitor) were dead after 5 days, and troleandomycin (a CYP3A-specific inhibitor) also reduced the survival rate. When cell homogenates were incubated with paraquat and NADPH, paraquat decreased and its metabolic intermediate paraquat-monopyridone was formed. Troleandomycin inhibited the decrease in paraquat and increased the monopyridone. After making a subfraction of the homogenate, monopyridone was produced in the postmicrosomal 105,000g supernatant, but not in the microsomes. The pretreatment of mice with phenytoin decreased the monopyridone in the postmitochondrial fraction, but did not affect the supernatant. These results indicated that paraquat was first metabolized in the postmicrosomal supernatant into monopyridone, and that may have been subsequently hydroxylated by the microsomes. Repeated intravenous injections of alpha-tocopherol to paraquat-loaded mice significantly reduced the paraquat mortality and when these mice were pretreated with rifampicin, 100% of them survived. These studies demonstrate that postmitochondrial fractions play an important role in paraquat detoxication metabolism, and that the combination of CYP induction and alpha-tocopherol administration is highly useful for the survival of paraquat-exposed mice.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Chromatography, High Pressure Liquid; Cobalt; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Enzyme Induction; Enzyme Inhibitors; Liver; Male; Methylcholanthrene; Mice; Mice, Inbred ICR; NADPH-Ferrihemoprotein Reductase; Oxidoreductases, N-Demethylating; Paraquat; Phenobarbital; Phenytoin; Proadifen; Rabbits; Rifampin; Troleandomycin; Vitamin E

It has been observed that growth of Escherichia coli cells are inhibited when treated with cobalt chloride (300 microM). It has also been shown that CoCl2 preferentially inhibits translation without inhibiting the process of transcription (1, 2, 8). We report here, that during treatment of E. coli cells with CoCl2, both messenger RNA and stable RNA synthesis is slowed down about 2.5 folds. The rate of degradation of mRNA also decreases and both chemical and functional half-life of mRNA increases about 2.5 folds in Co-treated cells. This clearly shows that the process of transcription is also affected while translation is preferentially inhibited during CoCl2 treatment.

Topics: Cobalt; Escherichia coli; Half-Life; Kinetics; Protein Biosynthesis; Rifampin; RNA, Bacterial; RNA, Messenger; Transcription, Genetic