Taleen Shakouri from the University of Hertfordshire, will be developing a computer model of certain toxicology tests which has the potential to replace many experiments currently conducted on primates and mice.

SUPERVISOR: Dr Stewart Kirton - University of Hertfordshire

STUDENT: Miss Taleen Shakouri

When people take medicines the body has to break them down so that it can get rid of the waste products. This works in a lock and key fashion, where the medicine which is the “key”, seeks out and combines with a molecular “lock” which then coordinates the removal of the waste.

However, some people are better at breaking these medicines down than others due to differences in their genetic makeup. These genetic differences in those who are less able to break down medicines causes the structure of their molecular locks to become slightly altered so that the key does not fit properly, and cannot be broken down. \Individuals who are unable to break down medicines at the normal rate are at risk of becoming unwell due to a build-up of pharmaceuticals over time in their body, and currently assessing whether or not a new medicine is likely to accumulate in the body relies heavily on testing with animals. This is not completely reliable as small changes in the structure of the “locks” between animals and humans can give misleading results.

This project proposes the development of sophisticated computational techniques to replace the use of animals for such testing. Using powerful software that mimics the thought patterns of the human brain we will analyse the components that make up the medicines and use this information to accurately predict if the medicine is likely to be problematic for those individuals who metabolise medicines at a reduced rate compared to normal.

Recent publications show the most commonly used animal models for CYP2D liability are mice, beagles and rats [1], [2] although primates are also routinely used [3], [4]. Work carried out in the UK used the liver microsomes of five marmosets to establish how similar the metabolic profiles of debrisoquine were to humans, in order to establish the validity of the marmoset as an appropriate animal model. Results were inconclusive [4]. This is not uncommon. It is often reported that the results obtained regarding the affinity for CYP2D6 and metabolite profiles from animal models used are different from human liver microsomal studies [3]. Consequently, genetically modified humanized animal models have been developed.

REFERENCES: [1] Y. Zhu i., ‘DDPH, a novel antihypertensive agent, is a potential dual inhibitor of hepatic CYP2D and CYP3A’, Chem. Biol. Interact., vol. 247, pp. 55–63, Mar. 2016.; [2] H. Nishimuta et al., ‘Species differences in hepatic and intestinal metabolic activities for 43 human cytochrome P450 substrates between humans and rats or dogs’, Xenobiotica, vol. 43, no. 11, pp. 948–955, Nov. 2013.; [3] I. Yamamiya et al., ‘Species variation in the enantioselective metabolism of tegafur to 5-fluorouracil among rats, dogs and monkeys’, J. Pharm. Pharmacol., vol. 66, no. 12, pp. 1686–1697, Dec. 2014. [4] B. R. Cooke et al.,‘Debrisoquine Metabolism and CYP2D Expression in Marmoset Liver Microsomes’, Drug Metab. Dispos., vol. 40, no. 1, pp. 70–75, Jan. 2012.