Wednesday, October 10, 2007

Bodily defense: detoxification update

Years ago as a budding toxicologist I studied a fascinating system called cytochrome P450, so called because under certain conditions one could measure a peak at the light wavelengths of 450nm. What was so fascinating was that it was, at the time, one of the few recognized detoxification systems. That is, this system, which consists of various proteins, could metabolize certain toxic chemicals and send them on their way out of the body. Now almost two decades later a recent paper, published in Developmental Biology by Goldstone and others, presents the “chemical defensome,” described as an “integrated network of genes and pathways that allow an organism to mount an orchestrated defense against toxic chemicals.” Though it sounds like something that belongs on a football field, it’s a little more highly evolved than that.

Back in the simple days, before scientists had the capability to identify each and every gene in our bodies, toxicology students studied the fate of fairly simple chemicals like polyaromatic hydrocarbons – those ubiquitous chemicals found in combustion products from the tip of a cigarette to the tip of your tailpipe – chemicals that basically sealed their doom by activating the system responsible for their own destruction. You see this particular detoxification system required activation or binding to a receptor, sort of the old lock and key - now an obsolete analogy but still good enough to get the basic idea across. A chemical binds to a receptor, and opens the door for specific proteins to be produced, in this case specific cytochrome P450 enzymes, which then go to work metabolizing the chemical sending it on its way to eventual detoxification.

Learning the story of P450 and polyaromatic chemicals was a must for nascent toxicologists. That was back in the old days, before the cigarette industry acknowledged the connection between inhaling a lungful of chemicals and cancer, but even back then we all knew that once some of those chemicals entered the lungs, little PAH keys entered PAH locks, or what we called aryl hydrocarbon receptors, activating genes necessary for P450 induction all around the body, in lung cells, liver cells, and kidney cells. We also knew that this process presented the proverbial “double-edged sword.” That is, detoxification of some chemicals, particularly PAHs, required several steps – some of them resulting in activation of a chemical to a more toxic or reactive state – before eventual detoxification and finally excretion. And, in the case of PAH, activation meant that the reactive PAH could bind to genetic material in way that could promote formation of cancerous tumors. We also knew there was a genetic component - even if we didn't know much about the genetics of the system. We knew then that the detoxification pathway proceeded differently and to different extents in some folks compared with others.

But at that time we were aware of just a few kinds of P450 enzymes, and, we had no idea of the breadth of the detoxification system, or the basic genetics of a system we now know we share with creatures ranging from tunicates, our slimy cousins that still cling to rocks by the seashore, to the pesky fruit flies that zip around the bruised fruit in my kitchen.

It made sense though, that given the harsh earthly conditions in which they evolved, our ancestors would need to protect themselves from constant chemical assault. But even so, back then, toxicologists wondered if receptors like the aryl hydrocarbon or PAH receptor evolved as a defense mechanism, or if its role in detoxification of foreign chemicals was a surreptitious side effect. Maybe, the system had evolved to deal with what are called endogenous chemicals, a way to get rid of the body’s own powerful chemicals once they no longer serve their purpose, like steroids for example (which, at least in my teen seems toxic enough, though to be fair, without them we’d probably still be clinging to rocks in some tide pool alongside our tunicate cousins.)

Now, a decade and a half later, scientists have unveiled a diverse and sprawling system of detoxification, or defense mechanisms from a plethora of P450 enzymes to antioxidants responsible for quenching the highly reactive oxygen produced by many metabolic processes protecting us from a range of potentially deadly chemicals, including microbial and plant toxins, PAHs and heavy metals.

In a paper that goes into genetic detail way beyond what my tunicate brain can comprehend, J.V. Goldstone and others introduce these systems collectively as a “defensome,” a fascinating concept of protective mechanisms that we humans take for granted, as we challenge our bodies with ever more complex combinations of naturally occurring and manmade chemicals. Let's just hope that unlike the typical Superbowl blowouts, we won't suffer a similar defensome overload, leaving us at the mercy of our natural and unnatural environment.

All the genetic details (and a hint to the youthful secrets of elderly sea urchins) can be found in Goldstone, J.V. et al. “The chemical defensome: Environmental sensing and response genes in the Strongylocentrotus purpuratus genome,” Developmental Biology 300:366-384.


A. Hamdoun said...

Thanks for the well written synopsis of our article and the excellent blog on toxicants.

One topic that relates to this article - and your blog - is how our knowledge of the defense mechanisms can be incorporated into regulation of industrial chemicals.

One idea, is to employ knowledge of the defenses to design chemical structures that are readily recognized and eliminated.

This might get around the "non-recognition" problem that seems to underlie the persistence of some chemicals such as DDTs and PCBs.

Emily Monosson said...

Interesting idea (designing chemicals for rapid detection and elimination.) I hadn't thought of "non-recognition" in terms of chemicals like DDT,PCBs and all the others that easily enter systems and accumulate or stick around.

But, I can't help but wonder - if this might be leading to chemicals that in some way or another create some unforeseen problem...overload of the system, increased defense byproducts with adverse effects etc?

Also, it's difficult (for me) to envision purposefully designing chemicals - with the intention of protecting against their release into the environment - rather than figuring out how to prevent release and exposure.

On the other hand what you suggest does make me think of nanomaterials since it seems inevitable that there will be release via production of certain products - if not already. Maybe nanomaterial structures could be at the very least, be engineered so that they are readily eliminated from living systems?

A. Hamdoun said...

One problem with the idea of overwhelming of defenses has been that many chemicals are present at very low levels in the environment or our bodies.

One possibility is that these chemical mixtures have additive or synergistic effects and there are some examples of that. Another is that the chemicals are interfering with signaling at very low levels.

However it seems that we will need both approaches to deal with the many types of chemicals out there - reduction of exposure and design of chemicals that do not accumulate.

The "green chemistry" approach can apply to chemical structures that are already in use and present in low amounts in the environment. Examples would be perfluorcarbons. Can we engineer these structures such that cells can safely eliminate them?

For chemicals that are widespread and highly toxic - eg mercury - the concern may be overwhelming of the defenses and the policy has to simply focus on reduction of environmental levels.

As you mention, nanomaterials are one example that everyone seems to be thinking about and how the cellular defenses deal with them is likely to be of major interest in the near future.