Threat of lipophilic hydrocarbons (Drug Biotransformational Systems – Origins and Aims (Human Drug Metabolism)

Organisms such as oysters that cannot rid themselves of lipophilic aromatic and nonaromatic hydrocarbons tend to accumulate these chemicals to toxic levels. Mudskippers, however, are less vulnerable to such toxicity as they use their biotransforming enzymes to remove these chemicals from their systems. With the advent of human dependence on petrochemical technology, vast amounts of lipophilic hydrocarbons are now a fixture of the air we breathe, as well as our food and drink. Dioxin (2, 3, 7, 8-tetrachlorodibenzo-p-dioxin; TCDD) is part of a series of polychlorinated dibenzo derivatives and it is one the best studied toxic lipophilic hydrocarbons. This herbicide contaminant demonstrates perhaps an extreme form of the threat of these molecules to all life on earth. Dioxins are not only carcinogenic and teratogenic endocrine disruptors, but also their half-lives in man can exceed 10 years. What is particularly worrying is that we have created molecules like dioxins of such stability and toxicity that despite the fact they actually trigger a potent cellular response intended to metabolize and clear them,we still cannot get rid of them quickly enough to protect ourselves.

Although dioxins are for humans a ‘worst case scenario’, the majority of living organisms including ourselves now possess some form of effective biotransformational enzyme capability which can detoxify and eliminate most hydrocarbons and related molecules. This capability has been effectively ‘stolen’ from bacteria over millions of years. The main biotransformational protection against aromatic hydrocarbons is a series of enzymes so named as they absorb UV light at 450 nm when reduced and bound to carbon monoxide. These specialized enzymes were termed cytochrome P450 monooxygenases or sometimes oxido-reductases. They are often referred to as ‘CYPs’ or ‘P450s’. CYPs may have evolved at first to accomplish reductive reactions in the absence of oxygen and they retain this ability, although their main function now is to carry out oxidations. These enzymes are part of a family whose functional characteristics are reminiscent of a set of adjustable spanners in a tool kit. All the CYPs accomplish their functions using the same basic mechanism, but each enzyme is adapted to dismantle particular groups of chemical structures. It is a testament to millions of years of ‘research and development’ in the evolution of CYPs, that perhaps 50,000 or more man-made chemical entities enter the environment for the first time every year and the vast majority can be oxidized by at least one form of CYP.

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