P450 CYPs and Capsaicin – a hot new way of simulating drug-metabolism outside the human body

Schüssel mit einigen roten Habanero-Chillischoten

Have you ever wondered, why it often takes many years until a new drug is available at your local pharmacy? One of the reasons is that the pharmaceutical industry wants to make sure that the drug is not only effective but also doesn’t produce toxic breakdown products that lead to undesireable side effects. Therefore, many time-consuming and not seldomly expensive tests are required to know precisely, which possible metabolic by-products could emerge. In a next step, the industry is producing such derivates to test them thoroughly for their side-effects, ensuring one goal: the patients health and wellbeing. To make drug development periods shorter and urgently required pharmaceuticals consequently faster available on the market in the near future, acib found a way to predict and prepare drug metabolites outside the human body.

Broken down: What are metabolites?

These mentioned by-products are also referred to as metabolites. Metabolites are products of active pharmaceutical ingredients made by human cells. Created from drug components with the help of enzymes, metabolites can possess various functions, e.g. structural, signaling, stimulatory and inhibitory effects on enzymes or regulating important metabolic steps in our body. Mostly, such breakdown and synthetic reactions on active pharmaceutical ingredients take place in the human liver, where over 500 different functions are performed. For drug metabolites, in other words, this is the place they are born. But, scientifically spoken, does it have “to be” this way?

An out-of-body experience:

In vitro simulation of drug-metabolizationIn order to shorten the time of structural elucidation of drug metabolites and toxological tests, the Austrian Centre of Industrial Biotechnology (acib) simulates – in vitro – the metabolization of drugs in the human body to offer the industry new drug development and production pathways. Unfortunately, it isn’t as easy as it sounds: Human enzymes are much more complex in comparison to microbial counterparts, they are also less easily accessible from microbial host systems and they may show less activity and stability. This especially is the case with human cytochrome-P450 enzymes, used by the acib-scientists. Here, the challenge is to produce them and their redox partners to be able to find the correct balance for preparing significant amounts of each compound in the subsequent production process.

To make scientific life a little bit easier, the acib-biotechnologists took a closer look at microbial cytochrome P450 CYP505X enzymes (CYPs). With these enzymes, they synthesized metabolites of Capsaicin, the active compound found in many heat wrap plasters. This drug was oxidized most efficiently in a whole cell mediated biotransformation.

Capsaicin – It’s hot!

Maybe you heard it’s name before: Capsaicin is the major pungent component of chili peppers and because of its sensory irritant properties, it finds application in pepper sprays and crop protection agents. Also, it is used in heat wraps for pain relief or as an agent for the treatment of arthritis, postoperative or neuropathic pain because of its anti-oxidant and anti-inflammatory activities. It turned out that the metabolites that were identified of capsaicin, are easier to prepare with microorganisms. They are now more accessible and microbial CYP partly resembles the metabolism of human CYPs. A huge success within the aim to provide alternatives to the repertoire of oxidative human enzymes and to reduce the time of future drug development periods.

“The research for this work has received funding from the European Union (EU) project ROBOX (grant agreement n° 635734) under EU’s Horizon 2020 Programme Research and Innovation actions H2020-LEIT BIO-2014-1” Any statements herein reflect only the author’s views. The European Union is not liable for any use that may be made of the information contained herein.”

Picture credits: Pixabay