Mammals, enzyme induction

The only information available on induction is an increase in ornithine decarboxylase (EC 4.1.1.17) activity in G. cydonium following field transplantation to polluted waters, viz. activity increased from 1.45 0.12 to 15.0 7.64 pmol min" mg protein over 24 days (Zahn et al. 1982). Ornithine decarboxylase is involved in polyamine synthesis and is induced by many stimuli in mammals this induction is one of the earliest events in the induction of MFO enzymes. 

Hodgson E, Kulkarni AP, Fabacher DL, et al. 1980. Induction of hepatic drug metabolizing enzymes in mammals by pesticides A review. J Environ Sci Health B 15(6) 723-754. 

In the early 1960s, during investigations on the N-demethylation of aminoazo dyes, it was observed that pretreatment of mammals with the substrate or, more remarkably, with other xenobiotics, caused an increase in the ability of the animal to metabolize these dyes. It was subsequently shown that this effect was due to an increase in the microsomal enzymes involved. A symposium in 1965 and a landmark review by Conney in 1967 established the importance of induction in xenobiotic interactions. Since then, it has become clear that this phenomenon is widespread and nonspecific. Several hundred compounds of diverse chemical structure have been shown to induce monooxygenases and other enzymes. These compounds include drugs, insecticides, polycyclic hydrocarbons, and many others the only obvious common denominator... 

Mechanism and Genetics of Induction in Mammals. Many different mechanisms may be involved in CYP induction. These include increased transcription of DNA, increased mRNA translation to protein, mRNA stabilization, and protein stabilization. Induction can only occur in intact cells and cannot be achieved by the addition of inducers directly to cell fractions such as microsomes. It has been known for some time that in most cases of increase in monooxygenase activity there is a true induction involving synthesis of new enzyme, and not the activation of enzyme already synthesized, since induction is generally prevented by inhibitors of protein synthesis. For example, the protein synthesis inhibitors such as puromycin, ethionine, and cyclo-heximide inhibit aryl hydrocarbon hydroxylase activity. A simplified scheme for gene expression and protein synthesis is shown in Figure 9.7. 

Hodgson, E., and Philpot, R. M. Interaction of methylenedioxyphenyl (1,3-benzodioxole) compounds with enzymes and their effects on mammals. Drug Metab. Rev. 3, 231,1974. Hodgson, E. Induction and inhibition of pesticide-metabolizing enzymes Roles in synergism of pesticides and pesticide action. Toxicol. Ind. Health 15, 6,1999. 

Two other types of regulation control the urea cycle allosteric activation of CPSI by 7V-acetylglutamate (NAG) and induction/repression of the synthesis of urea cycle enzymes. NAG is formed specifically to activate CPSI it has no other known function in mammals. The synthesis of NAG from acetyl CoA and glutamate is stimulated by arginine (Fig. 38.15). Thus, as arginine levels increase within the liver, two important reactions are stimulated. The first is the synthesis of NAG, which will increase the rate at which carbamoyl phosphate is produced. The second is to produce more ornithine (via the arginase reaction), such that the cycle can operate more rapidly. 

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