Enzyme induction inhibition

Ritz SA, Wan J, Diaz-Sanchez D (2007) Sulforaphane-stimulated phase II enzyme induction inhibits cytokine production by airway epithelial cells stimulated with diesel extractAm J Physiol 292(1 ) L33-L39. 

Ventricular dysrhythmias can occur Hepatic microsomal enzyme induction Inhibition of metabolism... 

Drug-drug interactions due to enzyme induction-inhibition... 

Emphasis is given to the critical role of metabolism, both detoxication and activation, in determining toxicity. The principal enzymes involved are described, including monooxygenases, esterases, epoxide hydrolases, glutathione-5 -transferases, and glucuronyl transferases. Attention is given to the influence of enzyme induction and enzyme inhibition on toxicity. 

Intake of various xenobiotics such as phenobarbital, PCBs, or certain hydrocarbons can cause enzyme induction. It is thus important to know whether or not an individual has been exposed to these inducing agents in evaluating biochemical responses to xenobiotics. Metabolites of certain xenobiotics can inhibit or stimulate the activities of xenobiotic-metabolizing enzymes. 

Some metabolites of curcumin (particularly tetrahydrocurcumin) may also participate in producing the observed effects of curcumin in different models because these metabolites display greater stabilities than the parent curcumin molecule at physiological pH. Recent data show similar modes of action of curcumin metabolites regarding antioxidant enzyme induction and inhibition of multidrug-resistant proteins. " Additional data indicate that curcumin may even act against other types of diseases such as atherosclerosis " " and Alzheimer s disease. " - " ... 

Only a small number of drug interactions have been reported with donepezil. In vitro studies show a low rate of binding of donepezil to cytochrome P-450 (CYP)3A4 or 2D6. Whether or not donepezil has the potential for enzyme induction is not known. No interactions with theophylline, cimeti-dine, warfarin, digoxin, or ketoconazole have been documented. In vitro studies show that inhibitors of CYP3A4 and 2D6 have the potential to inhibit the metabolism of donepezil. The clinical relevance of this is unknown. However, monitoring for possible increased peripheral side effects is advised... 

Vigilance for drug-drug interactions is required because of the greater number of medications prescribed to elderly patients and enhanced sensitivity to adverse effects. Pharmacokinetic interactions include metabolic enzyme induction or inhibition and protein binding displacement interactions (e.g., divalproex and warfarin). Pharmacodynamic interactions include additive sedation and cognitive toxicity, which increases risk of falls and other impairments. 

Enzymatic-metabolic activation (in part unknown)/phenobarbital-like promotion Hepatic enzyme induction, thyroid enzyme inhibition/axazepam, amobarbital, sulphonamides, thioureas Gastric secretory suppression, gastric atrophy induction (climetidine, omeprazole, butachlor... 

As indicated above in the section on "Genotoxic Effects", it is likely that mirex and chlordecone are tumor promoters and not tumor initiators. Initiators irreversibly alter DNA by a mutation, chromosomal aberration, or other alteration. Promoters act by facilitating the proliferation of previously initiated preneoplastic cells. One of the mechanisms for promotion is believed to involve suppression of inhibitory proliferative control through inhibition of gap-junctional-mediated intercellular communication as well as enzyme induction (Trosko et al. 1983). The results of studies to evaluate the promotional activity potential of mirex in mice indicate that mirex is a mouse skin cancer promoter but exerts this toxicity through a hitherto unknown mechanism that is different from that of phorbol esters, such as TPA (Meyer et al. 1993, 1994 Moser et al. 1992, 1993). Unlike initiation, promotion is a reversible process to a point. This implies, at least in theory, that there may be justification for setting NOAELs for promoters. 

First-pass clearance can be tracked to gut-stability or metabolism by phase I and then either direct clearance or clearance of the metabolite by phase It enzymes or biliary, renal or plasma clearance. Metabolite stability by phase I enzymes include inhibition, induction, regiospecificity, lability or affinity toward several cytochrome... 

Is the drug likely to he co-prescribed with a drug of narrow therapeutic index For example, a drug for angina, cardiac failure or an antiarrhythmic agent is likely to be co-prescribed with warfarin. If there is any evidence of enzyme induction or inhibition, a clinical study with warfarin may be required. 

Interactions with other drugs likely to be administered concomitantly, including enzyme induction and inhibition... 

Benedetti, M.S. (2000) Enzyme induction and inhibition by new antiepileptic drugs a review of human studies. Fundamental S, Clinical Pharmacology, 14, 301-319. 

---