Archive for July 6, 2011

Unusual Biotransformation of a Pyrrolotriazine Heterocycle

Biotransformations can be diverse and not limited to simple oxidation or dealkylation. An oncologic agent, The BMS-690514, is an example of unexpected metabolism. This compound undergoes multiple biotransformations, among them are P450 mediated oxidations of its heterocycle pyrrolotriazine group. Two major metabolites A and B are resulting from + O biotransformation.  However if the metabolite A shows a hydroxylation of the heterocycle, the metabolite B seems to undergone a unusual rearrangement. The isolation of that metabolite demonstrated the formation a hydroxypyridotriazine group.

This structure was confirmed using NMR spectrometry. The metabolism study of deuterium and tritium isotope label at the oxidized position showed that the label was retain during the formation of the metabolite A and lost during the formation of the metabolite B. The authors concluded that this metabolite was formed via epoxidation.

Haizheng Hong et al. Chem. Res. Toxicol. 201124, 125-134.

Mitochondrial Liabilities Assay and Metabolism with ICDD

Several recent papers have highlighted the importance of identifying mitochondrial liabilities to completely assess the toxicity potential of a drug (1-3).  Mechanisms by which drugs induce organ toxicity include the production of reactive metabolites (4).  Examples such as high-dose acetaminophen, which produces metabolites toxic to the mitochondria are found in the literature (5-8). 

Metabolites or cocktails of metabolites obtained through the Hepatochem technologies may act on one or several mitochondrial targets to induce mitochondrial impairment.  ROS production or reduced anti-oxidant defenses, perturbation of the bioenergetic balance, induction of permeability transition, depletion of mtDNA or reduced mitochondrial mass are some of the various targets that may induce mitochondrial dysfunction, loss of susceptible cell integrity & ultimately organ malfunctions and/or failure (7,9-12).  Using the MitoSafe line of functional bioassays developed by ICDD will demonstrate whether metabolites of your drugs induce mitochondrial liabilities in live-cell models.  Mitochondria toxicity is most readily expressed clinically by hepatic injury & cardio-toxicity, which can both be flagged through the study of your compounds and their metabolites with the MitoSafe bioassays.

Don’t hesitate to ask questions to our mitochondria

1- Marroquin LD, Hynes J, Dykens JA, Jamieson JD, Will Y. Toxicol Sci. 2007 ;97(2):539-47.

2- Dykens JA, Will Y. Drug Discov Today. 2007 ;12(17-18):777-85.

3- Begriche K, Massart J, Robin MA, Borgne-Sanchez A, Fromenty B.  J Hepatol. 2011 ;54(4):773-94.

4- Liebler DC, Guengerich FP.  Nat Rev Drug Discov. 2005 ;4(5):410-20.

5- Kostrubsky SE, Strom SC, Ellis E, Nelson SD, Mutlib AE. Chem Res Toxicol. 2007 ;20(10):1503-12.

6- Jaeschke H, McGill MR, Williams CD, Ramachandran A.  Life Sci. 2011 25;88(17-18):737-45.

7- Song Y, Shi Y, Yu H, Hu Y, Wang Y, Yang K. Toxicol Lett. 2011 ;202(1):55-60.

8- Chaudhuri L, Sarsour EH, Goswami PC. Environ Int. 2010 ;36(8):924-30.

9- Siu WP, Pun PB, Latchoumycandane C, Boelsterli UA.  Toxicol Appl Pharmacol. 2008 ;227(3):451-61.

10- Bai J, Nakamura H, Ueda S, Kwon YW, Tanaka T, Ban S, Yodoi J. J Biol Chem. 2004 ;279(37):38710-4.

11- Ramachandran A, Lebofsky M, Weinman SA, Jaeschke H.Toxicol Appl Pharmacol. 2011 ;251(3):226-33.

12- Zou W, Roth RA, Younis HS, Burgoon LD, Ganey PE. Toxicology. 2010 ;272(1-3):32-8.