I was saddened and surprised today to read this story on the BBC News website about a young man who died by overdosing on 2,4-dinitrophenol. Huh? Now, perhaps on account of my long hair and somewhat dishevelled appearance, I get offered a lot of drugs, but this isn't something I've ever heard hawked on street corners. It turns out that despite previous uses as a detonator and pesticide it's apparently quite popular among bodybuilders as a weight loss drug, something the FDA found it to be unsafe for back in 1938. Which is really something as 'safe' had a whole different meaning back then; hell, the 1948 the Nobel Prize for Medicine was awarded to Paul Müller for his discovery of 'wonder' pesticide DDT. But how does 2,4-dinitrophenol work? Well, here's a mechanism of action I wouldn't have guessed:
"DNP acts as a protonophore, allowing protons to leak across the inner mitochondrial membrane and thus bypass ATP synthase. This makes ATP energy production less efficient. In effect, part of the energy that is normally produced from cellular respiration is wasted as heat. The inefficiency is proportional to the dose of DNP that is taken. As the dose increases and energy production is made more inefficient, metabolic rate increases (and more fat is burned) in order to compensate for the inefficiency and meet energy demands. DNP is probably the best known agent for uncoupling oxidative phosphorylation."
Well, that sounds tempting! So, for a slightly higher basal metabolism you get a permanent fever, sweats and insomnia! Surprisingly, to me at least, mitochondrial uncoupling appears to be considered a valid approach for the development of anti-obesity drugs, despite these unavoidable side effects. The problem with using 2,4-dinitrophenol for this purpose is that the therapeutic index is very small, and overheating is quite easy even using a 'safe' dose, causing all kinds of problems. I read a few accounts of people's experiences with the drug online, and most of them concluded that taking 2,4-DNP was far more unpleasant than good old fashioned dieting. As Samuel Goldwyn once said, "gentlemen, include me out".