Methylcholanthrene microsomal enzyme induction

Treatment of mice or rats with phenobarbital significantly increases the rate of disappearance of exogenous bilirubin from the plasma which is accompanied by an increase in bile volume but no alteration in the concentration of bilirubin in the bile suggesting that the accelerated clearance results primarily from enhanced bile flow. However, there does not appear to be a direct relationship between increased biliary flow and microsomal enzyme induction because other enzyme inducers such as chlordane, nikethamide, phenylbutazone, 3-methylcholanthrene. 3,4-benzpyrene, or chlorcyclizine have no effect on bile flow. Other compounds whose rate of clearance from the plasma is accelerated by phenobarbital treatment are bromosulphophthalein (BSP), chlorothiazide, indocyanine green, probenecid, and chloramphenicol Enhanced clearance of the two latter compounds is associated with significant increases in the excretion of glucuronide conjugates. 

Treatment of animals with phenobarbital for 3—6 days increases the liver weight, the liver weight/body weight ratio, microsomal protein content, and the synthesis of microsomal protein. Induction with 3-methylcholanthrene is accompanied by a smaller increase in liver mass and increased synthesis of protein from labelled precursors. In addition to stimulating liva growth in normal animals, enzyme inducers increase the rate of liver regeneration following partial hepatectomy. 

On the basis of the early observation that the increases in microsomal enzyme activity produced by phenobarbital and 3-methylcholanthrene were blocked by actinomycin-D, it was suggested that enzyme induction resulted from the synthesis of new enzyme protein which was, in turn, dependent upon the DNA-directed synthesis of a messenger-like RNA. Treatment of rats with 3-methylcholanthrene causes an increase of about 40% in the level of RNA in rat liver nuclei and the nuclear RNA from 3-methylcholanthrene-treated rats is more active in directing protein synthesis than RNA from control animals. Moreover, the in vitro incorporation of radioactive precursors such as orotic acid or cytidine triphosphate into nuclear RNA is 50 to 100% greater in preparations from 3-methylcholanthrene-treated animals than controls. It is of interest that treatment of rats with phenobarbital has been recently reported to result in a marked suppression of endogenous hepatic ribonuclease activity. 

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