ROCHESTER HILLS, Mich.—2013 ended on a high note for Oxford Biomedical Research Inc. with the receipt of a $1,163,600 Phase 2 Small Business Innovation Research (SBIR) grant from the National Institute of Environment Health Sciences of the National Institutes of Health (NIH). The grant will support the development of a panel of tests designed to use GST proteins as sensitive, specific biomarkers to detect toxicity and determine potential toxic effects.
GST proteins are found in many tissues and organs, and when cells are exposed to toxic compounds, they produce small proteins such as GSTs, making them sensitive toxicity biomarkers. In addition, there are more than 20 GST proteins produced by different types of cells and tissues, so measuring multiple GSTs at once will enable rapid determination of which organ (or organs) displays the most toxicity sensitivity in the face of a drug candidate.
Together with Dr. Bengt Mannervik, an expert in GST biology, researchers at Oxford Biomedical led by Dr. Kevin Patrie have developed tests for a number of GST proteins. The National Institute of Environment Health Sciences-funded research will include the development of a device capable of rapid, economical measurement of multiple GSTs simultaneously. The potential of using GSTs for organ-specific toxicity testing will be validated by comparing them with conventional toxicity tests.
GSTs play a variety of roles, according to Dr. Denis M. Callewaert, founder of Oxford Biomedical, from playing a role in the production of prostaglandins and some steroids to excretion of toxins and drugs from the body.
“Historically, only three cytosolic GSTs were known—alpha, mu and pi—and in addition to their role in elimination of drugs, the levels of these enzymes in blood were found to be extremely sensitive biomarkers for liver or kidney toxicity; but they were not absolutely ‘organ specific,’ and other factors (e.g. diet) influence the levels in blood,” Callewaert explains. “Hence other toxicity biomarkers, e.g. ALT, have been much more widely used, even though these can suffer from poor sensitivity; by the time significant elevations occur, significant damage can have taken place.”
“We are developing antibodies and assays specific for each member of the GST family,” he notes. “This will allow us to clarify which cell types in which tissues make them. It is already clear that a couple of them can be used to distinguish damage to proximal kidney tubules versus distal kidney tubules.”
According to Callewaert, toxicity in general “is a very major problem,” as existing methods can fail to identify significant toxicity issues, such as ones that crop up only in a subpopulation of patients.
“A relatively high proportion of drugs have been recalled due to unanticipated adverse side effects,” he says. “Improved methods for the identification of potential toxic byproducts of drugs and differences in drug metabolism among individuals is needed to develop drugs more efficiently.”
He adds that GST proteins also have potential as diagnostics beyond the field of toxicity screening, though that is the initial intended application. Determining the levels of GSTs can be used to phenotype patients and identify those incapable of metabolizing certain drugs as quickly as other people. In addition, “There is also a lot of literature supporting a key role of GSTs in the prevention of cancer, and many healthy components of foods induce us to make more GSTs. So they may ultimately be useful in overall preventative medicine screening.”
Callewaert notes that they have been involved in this field for roughly 20 years, with their collaboration with Mannervik beginning four years ago. Mannervik, Callewaert points out, “pioneered the discovery and characterization of many of the previously unknown GSTs.”
This is one of almost 50 NIH grants and contracts the company has received over its 30 years in business, says Callewaert, supporting projects such as developing tools “to measure oxidative stress, phenotype cytochromes P450, screen for novel Cox-2 inhibitors, screen for drugs that may be activated by the COX enzymes to potential carcinogens and to measure the products of specific reactions.”