Combination treatment of epilepsy with ketogenic diet and concurrent pharmacological inhibition of cytochrome P450 2E1

Abstract

While most epileptic patients respond to treatment with existing antiepileptic drugs, there remains a considerable number of patients in whom these drugs do not suffice. Such patients, particularly children, are often treated using the ketogenic diet. This diet imposes a strict limit on carbohydrates; while providing for adequate protein, most of the calories are supplied as triacylglycerol, much of which is metabolized to ketone bodies.Animal experiments have provided evidence that the anticonvulsant effect of the ketogenic diet is mediated by acetone and correlates with acetone levels. Acetone can be converted in vivo to glucose via acetol and pyruvate; the initial conversion to acetol is catalyzed by cytochrome P450 2E1 (CYP2E1). When CYP2E1 knockout mice are subjected to starvation to induce ketogenesis, they develop blood acetone levels much higher than those observed in wild-type mice. Similarly, pharmacological inhibition of CYP2E1 significantly increases blood acetone levels in rat and man.Taken together, these observations suggest that pharmacological inhibition of CYP2E1 has the potential to significantly increase the antiepileptic effect of the ketogenic diet. With patients that respond insufficiently to the diet alone, increased acetone levels may improve response. With patients who respond sufficiently to the diet, CYP2E1 inhibitors might allow relaxation of the fairly severe diet regimen and so improve compliance and quality of life.An existing inhibitor of CYP2E1 is the drug disulfiram. This drug also inhibits the enzyme aldehyde dehydrogenase, which functions in alcohol degradation, and in this capacity has long been used in the treatment of alcohol addiction. Disulfiram inhibits CYP2E1 at conventional therapeutic dosages and increases blood acetone levels in humans and animals. It should therefore be a viable candidate for the proposed drug/diet combination treatment.2

Transcriptomic alterations in the heart of non-obese type 2 diabetic Goto-Kakizaki rats

“…It has been shown that 60 day old GK rats developed increased ketone body production [ 47 ], however, there is no literature data available about ketone body metabolism in the heart of GK rats. The ketone body acetone can be converted in vivo to glucose via acetol and pyruvate, and the initial conversion to acetol is catalyzed by Cyp2e1 [ 48 ]. It has been shown that Cyp2e1 knockout mice subjected to starvation to induce ketogenesis develop blood acetone levels much higher than those observed in wild-type mice [ 48 ].…”

“…The ketone body acetone can be converted in vivo to glucose via acetol and pyruvate, and the initial conversion to acetol is catalyzed by Cyp2e1 [ 48 ]. It has been shown that Cyp2e1 knockout mice subjected to starvation to induce ketogenesis develop blood acetone levels much higher than those observed in wild-type mice [ 48 ]. In our present study, the down-regulation of Cyp2e1 might be a possible cause of increased ketone body level in the myocardium, however, up-regulation of other genes involved in ketone metabolic process including Aldh1a1 ; Adh1c ; Akr1b10 ; and Akr1c12 may be an adaptive response in the myocardium to antagonize elevated ketone body levels.…”

Synergistic protection against acute flurothyl‐induced seizures by adjuvant treatment of the ketogenic diet with the type 2 diabetes drug pioglitazone

“…Pioglitazone is metabolized by CYP2C8 and CYP3A4, 26 but currently there is no evidence that the KD regulates these enzymes. Conversely, one of the metabolic pathways of the putative biochemical effectors of the KD, acetone and polyunsaturated fatty acids, involves CYP1 and CYP2 enzymes, which are inhibited by pioglitazone [27][28][29] ; thus, KD constituents could increase with adjuvant treatment with pioglitazone.…”

Effects of the 3.2:1 Ketogenic Diet on Behavioral Symptoms of Autism in the BTBR Mouse Model of Autism

“…Previous research has employed a combined treatment approach to epilepsy using both the ketogenic diet and pharmacological inhibition of CYP2E1, which causes an increase of blood acetone levels (a ketone that is also increased by the ketogenic diet). This increase in acetone levels may significantly increase antiepileptic effects of the ketogenic diet (Palmer, 2013). A similar approach could be taken with the 3.2:1 ketogenic diet and its ability to alleviate behavioral symptoms of ASD.…”