UC Systemwide Toxic Substances Research and Teaching Program

UC Toxics News: Fall 2003
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The Human Genome Project may have been completed recently, but scientists still have a long way to go before we understand individual variability in how our bodies interact with our environment. Genes are the basic framework for this understanding, but proteins are the workhorses - they are the enzymes that metabolize the compounds we encounter.

TSRT&P Trainee Erin Hsu is working on characterizing the CYP2S1 gene, which may play a significant role in how we metabolize inhaled toxics.

The lab of Oliver Hankinson, Director of the Toxic Mechanisms Lead Campus Program at UC Los Angeles, has identified a novel protein, CYP2S1, that may hold a key to how individuals react to certain environmental contaminants. Erin Hsu, a doctoral student in the Hankinson lab and TSR&TP trainee, is trying to functionally characterize this protein to determine what role it plays in biological systems. Does it create toxic intermediates from inert compounds when they are metabolized? Does it detoxify harmful compounds? Or both?

Hsu is working on identifying which substrates this protein acts on to determine what kind of effects it has in the body. She is making educated guesses on what compounds to test based on what they already know about the protein. "CYP2S1 is most highly expressed in the lung so that tells us it probably metabolizes particles in the air we breathe," explains Hsu.

There are an estimated 50-60 different forms of these cytochrome P450 enzymes in humans alone. The Hankinson lab demonstrated that CYP2S1 is inducible by dioxin. All other P450s that are inducible by dioxins metabolize polycyclic aromatic hydrocarbons (PAHs), common urban air contaminants. Hsu is honing in on PAHs to start. The lab is attempting to show that CYP2S1 metabolizes xenobiotics (foreign substances), but they are also interested in potential endogenous compounds, such as steroids and fatty acids that it may act on. "Uninduced or basal levels are very high compared with other P450 enzymes," says Hsu. "This most likely means the enzyme is doing something important in the body at all times."

Individuals are affected by compounds in different ways based on their genetic makeup, which results in different expression levels of these enzymes. Other enzymes in the cytochrome P450 superfamily have been shown to metabolize relatively non-toxic compounds to toxic intermediates, so it's a reasonable guess that CYP2S1 does too. "Once we have identified a functional role for this enzyme, preventative measures can be taken to avoid toxic responses and to improve therapeutic efficacy," says Hsu. "However, a significant amount of basic research is required before we get to the applied realm."

Hsu says her participation in the TSR&TP has enriched her graduate experience at UCLA. "What I like about this program is the exposure to other disciplines. It's refreshing to be updated with regards to recent findings in other areas of toxicology. It's easy to lose perspective when your research is in just one discipline. TSR&TP meetings remind us of our role within the greater field of toxicology."

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