ABC Transporter Primer

ABC Transporters serve a protective role and are responsible for the efflux of foreign molecules (e.g. drugs, xenobiotics) and naturally-occurring but unwanted substances (e.g. lipids) out of a cell.

Human ABC Transporters – for which there are 55 known genes divided into 7 subfamilies – are found in many different tissues including the brain, kidneys, pancreas, liver, skeletal muscles, and intestines as well as in immune cells such as macrophages. A few examples of ABC Transporters include: P-gP, ABCA1 and ABCG1. These protective pumps, located in cell membranes at select tissue barriers and organs, are specific for the types of molecules whose cellular removal they can facilitate. The energy for the efflux activity of ABC Transporters is derived from the hydrolysis of ATP.

BS (green) = binding site for LIM Activator
BS (red) = binding site for substrate of ABC Transporter

Not all harmful substances are substrates of ABC Transporters and hence are not effluxed out of the cell. This may result in its accumulation in multiple tissues (e.g., reduced tissue specificity) which may lead to toxicity in these exact tissues. While drugs or endogenous substances that are substrates for specific ABC Transporters are effluxed out of a cell, the rate of efflux may not be significant enough to mitigate its tissue toxicity properties. Accumulation of the body’s endogenous substances such as lipids may follow the same retention pattern in diseases such as hyperlipidemia or hyperglycemia, resulting in its abnormal accumulation inside various cells.

Limerick Activators are able to protect tissues and organs from toxicity by modulating the function of specific ABC Transporters to enhance the efflux of specific drug and endogenous substances from specific tissues and organs.

The concentration of drug or metabolite within a cell is dependent on the efficiency of its efflux from the cell.

There are three possible scenarios:

Non-Effluxed Molecules

If a drug or endogenous substance is not a substrate for ABC Transporter pumps, then Limerick Activators have no impact on its distribution.

Effluxed Molecules

If a drug or endogenous substance is a substrate for an ABC Transporter pump, its distribution may be impacted by a specific Limerick Activator. In its natural state, the pump functions to shift the distribution of its substrate from inside the cell back into the blood. Transport by the pump requires energy (hydrolysis of ATP).

Effluxed Molecules with Limerick Activator

If a drug or endogenous substance is a substrate for an ABC Transporter pump, the presence of a specific Limerick Activator increases its efflux via the activation of the ABC Transporter pump. Compared to the scenario of an effluxed molecule in the absence of the Limerick Activator, a greater efflux of the substrate from inside the cell back into the blood is seen in the presence of our Activator. Transport by the pump requires energy (hydrolysis of ATP).