Cell communication (Drug Biotransformational Systems – Origins and Aims) (Human Drug Metabolism)

Signal molecule design

At some point in evolution, single-cell life forms began to coalesce into multi-cell organizations, allowing advantages in influencing and controlling the cells’ immediate environment. Further down this line of development, groups of cells differentiated to perform specialized functions, which other cells would not then need to carry out. At some point in evolution, a dominant cellular group will have developed methods of communicating with other cell groups to coordinate the organisms’ functions. Once cellular communication was established, other cell groups could be instructed to carry out yet more specialized development. In more advanced organisms, this chain of command and control has two main options for communication: either by direct electrical nervous impulse or instruction through a chemical. Neural impulse control is seen where the sympathetic nervous system influences the adrenal gland by direct enervation. For an instructional chemical such as a hormone (from the Greek meaning to urge on) to operate, its unique shape must convey information to a receptor, where the receptor/molecule complex is capable of activating the receptor to engage its function. An instructional molecule must possess certain features to make it a viable and reliable means of communication. Firstly, it must be stable and not spontaneously change its shape and so lose the ability to dock accurately with its receptor. Secondly, it must be relatively resistant to reacting with various other cell enzymes or chemicals it might contact, such as proteolytic enzymes on the cell surface or in the cytoplasm. Finally, it must be easily manufactured in large amounts with the components of the molecule being readily available. It is immediately obvious that the pharmaceutical industry uses the same criteria in designing its products that often mimic that of an endogenous molecule. The final feature of an instruction molecule is that it must also be controllable. It is no use to an organism to issue a ‘command’ that continues to be slavishly obeyed long after the necessity to obey is over. This is wasteful at best, and at worst seriously damaging to the organism which will then carry out unnecessary functions which cost it energy and raw materials which should have been used to address a current, more pressing problem. The chemical instruction must be controlled in a period that is appropriate for its function. This might range from seconds to many years.

There are contradictions in this approach; the formation of a stable molecule which will be easily and quickly disposable. To make a stable compound will cost energy and raw materials, although to dismantle it will also cost the organism. It all hinges on for what purpose the instruction molecule was designed. For changes that are minute by minute, second by second, then perhaps a protein or peptide would be useful. These molecules can retain information by their shape and are often chemically stable, although the large numbers of various protease and other enzymes present at or around cell membranes mean that their half-lives can be exceedingly short. This allows fine control of a function by chemical means, as rate of manufacture can be adjusted to necessity given that the molecule is rendered non-functional in seconds.

Lipophilic hydrocarbons as signal molecules

Unlike short-term modulations of tissue function, processes like the development of sexual maturity require long-term changes in tissue structure as well as function and these cannot be achieved through direct neural instruction. Chemical instruction is necessary to control particular genes in millions of cells over many years. To induce these changes, hormone molecules need to be designed and assembled to be stable enough to carry an instruction (the shape of the molecule) and have the appropriate physicochemical features to reach nuclear receptors inside a cell to activate specific genes.

Lipophilic hydrocarbon chemicals have a number of advantages when acting as signalling molecules. Firstly, they are usually stable, plentiful and their solubility in oils and aqueous media can be chemically manipulated. This sounds surprising given that they are generally known to be very oil soluble and completely insoluble in water. However, those enzymes we inherited from bacteria such as CYPs have evolved to radically alter the shape, solubility and stability of aromatic molecules. This is in effect a system for ‘custom building’ stable instructional small molecules, which are easiest to make if a modular common platform is employed, which is usually the molecule cholesterol. From Figure 2.1 you can see the position of cholesterol and other hormones in relation to oil and water solubility, relative to a detergent, which is amphipathic, i.e. soluble in oil and water. The nearest agents with a detergent-l ike quality in biological systems are bile salts, which use this ability to break large fat droplets into smaller ones to aid absorption.

Cholesterol itself is very soluble in lipids and has almost zero water solubility so it requires a sophisticated transport system to move it around the body. Although a controversial molecule for its role in cardiovascular disease, it has many vital functions such as the formation of bile acids as well as maintenance of cell membrane fluidity. This latter function shows that cholesterol itself is so lipophilic that it is trapped in membranes. However, steroid hormones built on the cholesterol ‘platform’ are much less lipophilic than their parent molecule so they do not get trapped in lipid-rich areas, although from Figure 2.1 it is clear they are still not water-soluble. Highly lipophilic pollutant molecules like large polycyclic hydrocarbons are trapped within membranes and fatty tissue. Steroid hormones are synthesized so that they move through the circulation bound to the appropriate carrier molecule and then they can leave the blood to enter cells without being trapped within membranes.

The lipophilicity (oil loving) and hydrophilicity (water loving) of various chemical entities that can be found in living organisms

Figure 2.1 The lipophilicity (oil loving) and hydrophilicity (water loving) of various chemical entities that can be found in living organisms

They can then progress through the cytoplasm, binding various sensor molecules associated with the nucleus. Thus, their information is conveyed intact to instruct the cell. Once the stable steroid platform has been built by CYPs and served its purpose, the final link in the process is the use of various other CYPs to ensure the elimination of these molecules. The complete synthesis and degradation system is fully adjustable according to changing circumstances and can exert a remarkably fine control over steroid molecules. Such is the efficiency of this system that early human contraception studies showed that after an oral dose of oestradiol-17ß, systemic bioavailability was virtually zero.

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