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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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August 27, 2006

Floyd Landis: Could His Cortisone Treatments Exonerate Him?

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Posted by Derek

After my article on the role of carbon isotope testing in the Floyd Landis case, a question has come up several times in the comments and in my e-mail: since it's well-known that Landis was taking cortisone for his hip, could this have skewed the isotope ratios in his testosterone?

I doubt it very much, and here's why: first off, around 95% of the circulating testosterone in the male body is produced in the testes. For Landis's isotope ratios to be off a significant amount through something involving his own metabolic pathways, this is the only place that's worth looking.Testosterone and the other steroids are produced from cholesterol. The testes and other steroidogenic tissues have a stockpile of cholesteryl esters ready to be used for steroid synthesis, so it's going to be an uphill fight to alter things by any route, given that reserve.

Now it's time to dive into some biochemistry for the next few paragraphs - follow along if you like, or jump down to near the end if you don't want to see a lot of structures. OK, in steroid synthesis the first thing that happens is the chewing off of a side chain on the D ring to form pregnenolone, which is then turned into progesterone. That's the starting material for both testosterone and cortisol/cortisone. (Note that those last two are interconverted in the body by the 11-HSD enzymes).

Going down these different pathways, testosterone and cortisol end up with rather different structures. Cortisol's more complex. If you flip back and forth between those links in the previous paragraph, you'll see that the A and B rings are the same in both, but the C ring of cortisol has an extra hydroxyl group at C11, and it also has some oxidized side chain left at C17, which has been completely chopped off in testosterone. The question is, can you get from cortisol back to something that could be used to make testosterone?

I can believe the side-chain transformation much easier than the C-11 deoxygenation. Here's the metabolic fate of cortisol. Note that all these metabolites still have an oxidized C-11 - if anything is going to be recycled into testosterone, that C-11 is going to have to be reduced back down. And if there's a metabolic pathway that does that to any degree, I can't seem to find out anything about it. If it's a feasible pathway at all, it must be very minor indeed. If any steroid experts can shed light on this, I'd be glad to hear the details. (There's also the question of how long such intermediates would be available, versus their half-life before further metabolism and excretion, but that's a whole other issue).

No, if Landis's carbon isotope ratios are off significantly - and we haven't seen the official numbers yet - then it's hard for me to see how the cortisone injections could have much to do with it. We'll be stuck, in that case, with either conspiracy theories or with the conclusion that Landis used testosterone, and if it comes to that, I know which one I'm most likely to believe.

Comments (22) + TrackBacks (0) | Category: Analytical Chemistry | Current Events


COMMENTS

1. Mark Neumann on August 27, 2006 11:11 PM writes...

I have read that Floyd's (The MAN) testosterone levels were normal and his epitestosterone levels were low, and that the test for synthitic sp. were at a non detect level. Doesn't this clear him?

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2. Roid Rage on August 28, 2006 8:20 AM writes...

The test for synthetic testosterone (T) is a ratio comparing the C13/C12 of the testesterone pathway with another unrelated steroid (e.g. pregnane). As you say, if T is normal, then the ratio would never be undetectable, but rather within the reference range or outside that expected ratio (for this test that is 3 standard deviations or ~=99.73% certainty). To my knowledge, the actual numbers have never been released or leaked. The bottom line is this: the test is excellent, his only reasonable defense would be sabotage.

None of these doping scandals make the Tour any less interesting in my opinion, and I look forward to next years race.

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3. John Westin on August 28, 2006 11:18 AM writes...

Do soy-proteins affect T/E levels? Most protein supplements use soy-based protein, I believe.

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4. MJK Boston on August 28, 2006 12:00 PM writes...

So I really want to believe Floyd is innocent and this is some type of covert plot but........ if he were doping with testosterone over a period of time (not just a one-time drunken application) it is my understanding that he would be getting boosted for both T and E in order to keep the ratio from setting off the alarms. If something happened to boost his T (like his body naturally producing extra after beer/Jack Daniels binge and extraordinary bike ride in Stage 17) before he could get more E, could that have put him over the edge? Was he caught not doping enough to manage his ratio?

Does anyone know if in the body naturally does E always track T at the same level?

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5. SC on August 28, 2006 12:23 PM writes...

From my understanding as well, his testosterone levers were fine, but epitestosterone levels were low, making his ratio outside of acceptable ranges, but for reasons that are subtly different than most athletes that cheat.

There seems to be a huge issue here - he was tested on a few occaisions during the race with a normal ratio, and neither level outside of the usual range. Now he has a low epi-T level, that throws off his ratio. Doping (Testosterone-based, anyhow) at that stage of the race would result in high testosterone levels, not low epi-testosterone levels, and in any case, would not be expected to provide that significant a boost that quickly.

I am therefore forced to wonder about a couple of alternatives - either he blood doped (whole blood, taken from himself months ago, frozen to store, thawed after the disastrous stage then reinfused, but during the process, enough metabolism of the epitestosterone to throw off the ratio) or the lab has a problem with consistency.

I am not one for conspiracy theory, so I don't want to suggest that either the French or American s have a monopoly on ethics (or lack thereof) - both have a huge financial stake. I do get the impression, though, that Floyd isn't being given the opportunity to be heard fairly.

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6. David Brower on August 28, 2006 1:46 PM writes...

On href=http://groups.google.com/group/rec.bicycles.racing/browse_frm/thread/3b5978396cd36345/1dd3ca3e6c79fe2d?lnk=st&q=floyd+landis&rnum=1#1dd3ca3e6c79fe2d)> USENET , this post provoked some responses below, which I'll summarize as, "some research shows quick effect of diet/alcohol on c12/c13, possibly exacerbated by metabolic turnover during a grand tour; please consider these factors."

Some of the partial responses:


"Testosterone and the other steroids are produced from cholesterol. The testes and other teroidogenic tissues have a stockpile of holesteryl
esters ready to be used for steroid synthesis, so it's going to be an uphill fight to alter things by any route, given that reserve."


Obviously, that statement is true for "normal" people. However, is that statement true for an elite athlete 2.5 weeks into a grand tour? If it is so, why are T levels typically lowered due to the stress of the efforts? Do we know if that "reserve" is present in that case, or are the testes basically "scrambling to get any building materials they can get their hands on"?


Also, how does that statement jive with WADA's own study (as mentioned by Mr. Fine) which found that C12/C13 ratios could be altered quickly just from diet alone?

http://www.bgc-jena.mpg.de/service/iso_gas_lab/gasir2005/GasiR_2005_Program_and_Abstracts.pdf

Also, referencing some data provided by Tom Fine http://groups.google.com/group/rec.bicycles.racing/browse_frm/thread/3b5978396cd36345/1dd3ca3e6c79fe2d?lnk=st&q=floyd+landis&rnum=1#1dd3ca3e6c79fe2d
and http://hea-www.harvard.edu/%7Efine/opinions/testosterone_d13C.html


And this paper identified by http://freefloydlandis.blogspot.com

(Short communication: Christophe Saudana, Matthias Kamberb, Giulia Barbatic, Neil Robinsona, Aurélien Desmarcheliera, Patrice Mangina and Martial Saugya. Longitudinal profiling of urinary steroids by gas chromatography/combustion/isotope ratio mass spectrometry: Diet change may result in carbon isotopic variations. Journal of Chromatography B, Volume 831, Issues 1-2 , 2 February 2006, Pages 324-327.)

I'm trying to keep a roundup of Landis related news and comment at http://trustbut.blogspot.com.

-dB

Permalink to Comment

7. bill on August 28, 2006 3:44 PM writes...

what if he fell asleep drunk with a testosterone patch on his willy?

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8. Luke, I am your fungus! on August 28, 2006 8:25 PM writes...

what if he got drunk and ate Tampax from a girlfriend who is body-building?

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9. Darksyde on August 30, 2006 1:42 PM writes...

Conspiracy: Well, everyone says that there are "rules in place" to ensure that the samples don't get swapped, or what not.

1) the rules are generally contrived to prevent false negatives, not false positives. An engineered positive (say, someone adds synthetic T to his tubes *before* he pissed into them) show up as -- well excess T over epi-T, and a failed CIR.

2) The rules were clearly broken when they broke the news about Landis way too early (he learned himself from the news). It's clear that the officials don't have any regard for him or any presmuption of innocence.

The fact of the matter is that Landis tested positive by the rules and rules are rules. He should give up his medal, and then go on a mega-rampage when they find out that he'd been framed.

Permalink to Comment

10. david brower on August 30, 2006 7:33 PM writes...

Since there are chemists here, let me ask you a few questions.

1. What would it take to convince you that the measured results came from an innocent natural process?

2. What would it take to convince you that there was something wrong done in the analysis to call the results into question?

3. What questions would you ask to get information that would get you to Q2?

Note that there has still been no distribution of the formal report with the actual quantitative findings, and that there isn't even a USADA case against Landis at this time.

thanks,

TBV http://trustbut.blogspot.com for Landis news

Permalink to Comment

11. weirdo on September 3, 2006 10:55 AM writes...

My answers to questions in #10:

1) If the reported results are accurate: Nothing.

2) If the samples were re-tested in another lab with significantly different results, all bets are off.

3) See the answer to #2. Re-test the same samples elsewhere.

Tampering -- adding exogenous testosterone to the tubes, etc. -- would be very difficult to detect. Theoretically, one could look for all the metabolites of testosterone and determine their isotope ratios. If they are not off, then the T was never in Landis' body. But I'm not sure those analyses are even validated.

Permalink to Comment

12. david brower on September 4, 2006 10:14 PM writes...

Thanks, weirdo.

I take your points about 2 and 3, but I'm curious about your faith in the raw data as being c ompletely conclusive for question 1.

This is a hypothetical, of course, but suppose Landis did a three day race simulation including a bonk and a night of ethanol consumption, taking samples all along the way. Suppose the sample after the last day was close in values to those reported for the stage in question. Could that be taken as experimental proof that the result was a natural production, and demonstrate there there are some things about the physiology we don't understand?

Of course, this test hasn't been run, and might not turn out that way. The question is whether such a test and result would suffice to prove the point. If we grant that that might, are there other tests we might imagine that would be easier to run that could produce enough data to be convincing?

thanks,

-dB http://trustbut.blogspot.com for Landis news, research, and comment

Permalink to Comment

13. roidrage on September 5, 2006 4:19 PM writes...

re: 10

It would take some remarkable science to convince me that something other than exogenous testosterone could give a positive carbon isotope ratio restult.

The key piece of information that nobody mentions is that the ratio is compared with an endogenous internal standard i.e. an unrelated steroid (e.g. pregnanediol, or cholesterol etc.).

The chances of finding a legal compound that selectively changes the T isotope ratio and doesn't affect the ratio of unrelated internal standards is practically nil.

If the sample was tampered with, the whole testing lab and accreditation agency would have to be corupt and there is no lab test for either of these.

Has anyone considered the possibility that Landis took testosterone?

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14. ROb on September 6, 2006 11:52 AM writes...

Yeah, I think he doped with T. But the question is, why? There would be no performance benefit for doping w/ T, and so much downside, ie possible striping of TdF title. So that is the thing that doesn't make sense. If he knew he wouldn't gain anything, and did it anyway, then he's very stupid. Or it's something else going on, something natural.

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15. Nancy on September 10, 2006 6:45 PM writes...

Is it possible he could have eaten meat or other food in which the animal had ingested steroids that could have caused the increase in his testosterone?

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16. janet on September 12, 2006 10:43 AM writes...

Floyd having hip injection before tour, did anyone check (i doubt it) what steriod he was given ,if it was depo medrol which is said can go into soft tissue and joint as Kenalog or Cele-soluspan so they say, which i would never trust, because i was disabled by and epidural steriod inj for sciatica only finding out it is not approved by the FDA for the spine it caused adhesive arachnoiditis the perseratives in this are in anti freeze, brakefluid, ink, freon, we are not told of the risks of this or what the drs inject, so check it out before getting and ESI for childbirth, spinal inj for sciatica or back and leg pain , it causes a debillitaing pain that is continous 24/7 no cure for this pain, u cannot walk far sit long stand or work again, u get stabbing pain in feet legs, back knife like pain, u get muscle spasms in back leg feet swell, toes go into a lock position and arch of feet go into pain and spasms and curl up like u are crippled,some people say their feet feel like they are walking on glass www.cofwa.org and then how crooked the Fda is go to www.biospace.com and read this about a pump, so the neurotoxin hits right spot, targeting pregnant women back and leg pain sufferers if the depo medrol which is a neurotoxin is not approved for the spine why would the morons at the Fda approve a pump for this. after 33 pain meds 29 drs 7 mri c scans 2 emg tests for nerve damage and exrays bone scan, nerve block with the DM found out later and 3 unessary back surgery to get pain relief ,only got worse so they will not tell u about this. the risks are not disclosed scientists are superficial like the FDA ths DM data sheet from upjohn and pharmacia now connected with Pfizer tells u for animals not humans be safe not sorry, i believe Floyd is inicent and they did not want another american to win again, did they test all the losers? hum makers u wonder PS this DM also causes SJS so while one steriod suppose to build u up, another can tear u down. Floyd is innocent he need to find out what he was injected with.

Permalink to Comment

17. Thomas A. Fine on September 13, 2006 2:54 PM writes...

Hi,

There's just one critical thing you missed.

The metabolites of cortisol are among those metabolites used by WADA as references to give a baseline of comparison with the testosterone metabolites. In other words, the cortisone he was taking didn't convert somehow to testosterone. His (possibly synthetic) cortisol metabolites would be compared directly to his testosterone metabolites.

tom

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18. John Dennigan on October 10, 2006 5:38 PM writes...

Hey, I thought everyone would be interested in this. Read the article "Catchy Carbon" in the November issue of Scientific American about the accuracy of the CIR test."...if the body were able to make testosterone from an artificial compund-such as the cortisone athletes sometimes inject to reduce muscle inflammation-might the natural hormone carry a synthetic-looking finger-print, Hayes notes." Wasn't Floyd taking regular cortisone injections for his hip pain? Can't this explain the CIR test results?

Permalink to Comment

19. Jack Byrom on December 3, 2006 3:23 PM writes...

More in regards to the Nov. 2006 Scientific American article. How disappointing that this journal`s editor chose to go with a story that casts further doubt upon an unfairly treated man when there were definite alternatives for a good Landis story. For instance, what about the scientific aspects of the controversy caused by the French national (Châtenay-Malabry) drug-testing lab, such as: 1. recurrent accusations of poor scientific procedures within the lab. 2. Lack of respect for confidentiality involving high-stakes, high-profile cases. 3. Rampant hysteria in the press regarding cycling doping allegations.
Instead, the American cyclist just got more "science-based" bad press, definitely giving the impression to the average reader that Landis (or Tyler Hamilton, or Lance Armstrong) is guilty, before proven innocent. SciAm: science does not exist in a vacuum. You could have taken another angle on this for your first shot.

Ohio, USA

Permalink to Comment

20. Jack Byrom on December 3, 2006 3:25 PM writes...

More in regards to the Nov. 2006 Scientific American article. How disappointing that this journal`s editor chose to go with a story that casts further doubt upon an unfairly treated man when there were definite alternatives for a good Landis story. For instance, what about the scientific aspects of the controversy caused by the French national (Châtenay-Malabry) drug-testing lab, such as: 1. recurrent accusations of poor scientific procedures within the lab. 2. Lack of respect for confidentiality involving high-stakes, high-profile cases. 3. Rampant hysteria in the press regarding cycling doping allegations.
Instead, the American cyclist just got more "science-based" bad press, definitely giving the impression to the average reader that Landis (or Tyler Hamilton, or Lance Armstrong) is guilty, before proven innocent. SciAm: science does not exist in a vacuum. You could have taken another angle on this for your first shot.

Ohio, USA

Permalink to Comment

21. Lusidvicel on December 18, 2006 11:52 AM writes...

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22. Anonymous on November 16, 2007 5:10 PM writes...

Sorry :(

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