Enzyme induction substances causing

Urinary D-glucaric acid levels have been shown to be a sensitive indicator of microsomal enzyme induction in workers exposed to chlordecone (Guzelian 1985). However, other substances such as barbiturates, phenytoin, chlorbutanol, aminopyrine, phenylbutazone, and contraceptive steroids as well as other organochlorinated pesticides also cause microsomal enzyme induction and cause changes in urinary D-glucaric acid (Morgan and Roan 1974). 

There is no evidence that tibolone causes enzyme induction. In theory, substances that induce cytochrome P450 may affect the metabolism of tibolone and lead to reduced activity. However, no interactions between tibolone and other medicines have been reported in clinical practice [7]. 

Enzyme induction by drugs and other substances (see p. 113) accelerates metabolism and is a cause of therapeutic failure. The following are examples ... 

Induction observed The substance evaluated is observed to cause dose-dependent and physiologically significant induction (e.g., induced activity over twofold of negative control activity). If the doses found to be positive are within clinical plasma concentrations (e.g., within lOx of plasma Cmax), in vivo studies may be needed to further define the test article s in vivo enzyme induction and the subsequent drug-drug interaction potential. 

Drugs that cause induction or inhibition of enzymes may affect the metabolism of concomitantly administered drugs, as well as of hormones and other endogenous substances. For this reason, such properties are considered undesirable and sometimes they might constitute sufficient reason to discontinue drug development. At the very least, studies will be required to assess the magnitude of effect of likely interactions. Metabolic and toxicity studies in animals will usually provide the basis for suspicion, and studies in human liver slices, cultured hepatocytes and microsomal preparations can be extremely valuable in establishing metabolic pathways and the likelihood of enzyme induction or inhibition in man. There have been some important developments in this field in recent years and it is now possible to identify ... 

Dioxin, PCB, DDT, and the like, i.e., chlorinated aromatic hydrocarbons are believed to bind to a special receptor called AH receptor (AH stands for aryl hydrocarbon). The AH receptor bound with dioxin (or PCB) enters into the nucleus of the cell, and binds to a specific site of a DNA. One of the effects caused by such a binding seems to be an induction of an enzyme dependent on cytochrome P-450. Cytochrome P-450-dependent monooxygenase was talked about in Sect. 6.2.2, and is involved in the metabolism of a wide variety of compounds including steroids and foreign substances (drugs). Probably the P-450 enzymes induced by dioxin, PCB, and others would then metabolize steroid hormones unnecessarily, and thus disrupt the endocrine system. The details are still not very well understood. However, you see that the processes are all chemical reactions at the deepest level. 

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