Implications of Enzyme Induction and Inhibition

Patients are often given several drugs at the same time. The possibility that one drug may accelerate or inhibit the metabolism of another should always be kept in mind. When this phenomenon occurs, the removal of an enzyme inducer could be hazardous. The following examples reveal the consequences of enzyme induction. 

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Park, B.K. Kitteringham, N.R. (1990) Assessment of enzyme induction and enzyme inhibition in humans toxicological implications. Xenobiotica, 20, 1171-1185. 

Ceramides are intracellular signaling molecules implicated in the induction of cellular apoptosis (Kolesnick and Krbnke, 1998 Hannun and Luberto, 2000), and are known to induce several protein kinases and phosphatases (Mathias et al., 1991 Dobrowsky et al., 1993 Vietor et al., 1993). Ceramide analogs have been shown to inhibit PC synthesis (Bladergroen et al., 1999 Allan, 2000 Ramos et al., 2000 Vivekananda et al., 2001). Ceramides may directly affect the biosynthesis of PC and phosphatidylethanolamine (PE) by inhibiting the enzymes of the CDP-choline and CDP-ethanolamine pathways (Bladergroen et al., 1999 Awasthi et al., 2001 Ramos et al., 2002). 

Phytoalexins can be elicited in plants by a variety of agents, including viruses, microorganisms and nematodes [292, 293]. When resistant plants are infected by nematodes, phytoalexins with antinematodal activity can be produced [294]. Some coumestans have been implicated in the resistance of plants to nematodes. For example, when the roots of the resistant lima bean (Phaseolus lunatus) were inoculated with Pratylensus scribneri, coumestrol (181) accumulated at the site of nematode attack. In vitro, coumestrol (5 ig/ml) inhibited the motility of the nematode [294]. Correlative evidence for a functional role of related compounds in resistance towards nematodes has been obtained [295-297]. In particular, nematode attack on the roots elicits the transcription of genes encoding several enzymes of the shikimate pathway that leads to phytoalexin production. Induction of enzyme activity results from transcriptional activation of the genes leading to increased levels of translatable mRNA [298]. 

Under normal conditions, induction and catabolite repression together insure that inducible enzymes are only produced in the presence of substrate but that when several substrates are present, only the enzymes acting on the best substrate are formed. Very recent studies implicate inhibition of cyclic 3, 5 -adenosine monophosphate formation as the key factor in catabolite repression (Perlman and Pastan, 1969). Cyclic 3, 5 -adenosine monophosphate reverses catabolite repression of many enzymes in E. coli and its intracellular concentration is depressed 1000-fold by growth on glucose. 

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