June 2012

Sports doping sidebar: molecular quirks

 

Molecular biology presents interesting riddles to the antidoping world. An example is the story of Finnish cross-country skier Eero Mäntyranta. Mäntyranta won three gold medals in the Winter Olympics of 1964 and was suspected of doping. Tests showed that he had 15 percent more red blood cells than normal, but he didn’t have signs of blood doping.

In 1993, the group of Albert de la Chapelle at the University of Helskini in Finland demonstrated that a genetic mutation produced a truncated erythropoietin receptor (3). Mäntyranta carried the mutation. In 1995, Harvey Lodish’s group at the Whitehead Institute showed this truncated receptor was insensitive to a feedback loop that would turn it off. The receptor’s malfunction meant that the bone marrow produced more red blood cells than normal (4) (see References in main story).

Don Catlin at Anti-Doping Research gives another example of molecular biology complicating doping detection. For the testosterone-detection technique developed by Catlin’s group, the test looks at the ratio between testosterone and epitestosterone, a version of testosterone that has no known function. In normal men, the ratio is 1:1. But in an athlete doping with testosterone, the ratio goes up. WADA sets a T/E ratio of 4:1 or higher as the possible sign of doping.

In developing the test criteria, Catlin noticed that the testosterone levels in some of the Asian male study participants never fluctuated, even though he knew he was injecting them with synthetic testosterone. In terms of doping, this would give certain athletes “a license to steal,” says Catlin.

For testosterone to be excreted in urine, it has to be first turned into a glucuronide conjugate by uridine diphospho-glucuronosyl transferases. Catlin began to suspect these Asian men had deletions in one of these enzymes.

In 2006, the group of Anders Rane at the Karolinska University Hospital in Sweden published findings that explained Catlin’s observations. Rane’s group described how double deletions in the gene for UGT2B17, the enzyme that does most of the glucoronide conjugation to testosterone, led to differences in testosterone excretion between Korean and Swedish men. The Asian men had very low T/E ratios (5) (see References in main story). The polymorphism is almost seven times more common among Koreans than Swedish Caucasians.

 

Raj_MukhopadhyayRajendrani Mukhopadhyay (rmukhopadhyay@asbmb.org) is the senior science writer for ASBMB Today and the technical editor for The Journal of Biological Chemistry.


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