This lecture focuses on the genetic polymorphism of human thiopurine methyltransferase,
and the influence these genetic polymorphisms have on thiopurine therapy,
and the lecture will span from molecular genetics to
the clinical application of these diagnostics
in prescribing and individualizing therapy with thiopurines.
Thiopurines include azathioprine, which is a prodrug for mercaptopurine,
as well as mercaptopurine,
a widely used antileukemic agent, and 6-thioguanine,
which is also affected by this polymorphism,
although perhaps less dramatically.
Each of these medications is inactivated through
methylation by this polymorphic thiopurine methyltransferase enzyme,
and it's been shown that individuals who
inherit low activity of thiopurine methyltransferase
have an increased risk of toxicity if
treated with the conventional doses of mercaptopurine,and azothioprine
and to some extent thioguanine.
This slide depicts the metabolism of mercaptopurine,
abbreviated MP in this slide,
which indicates that this medications either activate it to thioguanine nucleotides,
abbreviated TGN, by a multi enzymatic process,
the first step of which is catalyzed by the enzyme HPRT,
or this medication is inactivated either by methylation catalyzed by TPMT,
or by the enzyme xanthine oxidase.
Both of those enzymes convert mercaptopurine to
inactive metabolites that cannot be further activated.
In many tissues, the inactivation is controlled by both xanthine oxidase and TPMT,
but in hematopoietic tissues,
xanthine oxidase activity is very low, if at all,
meaning that the inactivation is determined by TPMT,
and the activation is determined by HPRT.
In that case, you would predict that patients who lack
TPMT activity would not inactivate the drug as well,
and they would shunt more drug down the activation pathway and
accumulate more of the active thioguanine nucleotide metabolites.
This slide depicts the same metabolic pathway as on the previous slide,