Finally, an in vitro study (10) suggested an alternative biochemical mechanism: XO inhibition by allopurinol may lead to preferential 6-MP oxidation via aldehyde oxidase, with the production of dihydroxy-6-MP, a compound responsible for feedback inhibition of TPMT activity.
6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease.
A 53-year-old woman with Crohn disease receiving 6-MP
monotherapy underwent liver biopsy for investigation of elevated aminotransferases.
But when the women on azathioprine or 6-MP
were compared with women with IBD who were not on one of the purines, there was no increased risk in malformation - which indicates that it is not prenatal exposure to azathioprine or 6-MP
but the condition itself that may increase the risk of malformations to some extent.
Limitations to the present study include the lack of standardized dosing of AZA or 6-MP
and the lack of clinical correlation.
9] Nonstandard abbreviations: AZA, azathioprine; 6-MP
, 6-mercaptopurine; 6-TGN, 6-thioguanine nucleotide; 6-MMP, 6-methyl mercaptopurine; TPMT, thiopurine S-methyltransferase; Ery, erythrocyte; CDAI, Crohn disease activity index; IBDQ, Inflammatory Bowel Disease Questionnaire; ITT, intention-to-treat; MCV, mean corpuscular volume.
To our knowledge, reports evaluating potential differences between aza and 6-MP
with regard to ITPA-related thiopurine intolerance have not been published.
In this series, patients homozygous for mutant low-TPMT-activity alleles tended to develop severe myelosuppression often and early, within the first 4-6 weeks on azathioprine or 6-MP
TPMT irreversibly transfers a methyl group from S-adenosylmethionine (SAM) to 6-MP
, forming 6-methylmercaptopurine (6-MeMP) and S-adenosylhomocysteine (SAH).
and azathioprine therapy can cause myelosuppression.
The influence of 6-MP
and SAM concentrations on TPMT activity was assessed using eight concentrations of 6-MP
3]H-labeled methyl group in S-adenosyl-methionine to 6-MP
over 1 h at 37[degrees]C was followed by [beta]-scintillation counting after extraction of the product (6-methyl-MP).
Then, high 6-TGN concentrations in RBCs could be correlated with low erythrocyte TPMT activity, which exhibits a favorable clinical outcome in children with acute lymphoblastic leukemia treated by 6-MP
is activated intracellularly by the conversion of 6-MP
into thio-IMP (tIMP) by the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase [3, 4].
is further converted in the liver and gut to 6-thioguanine nucleotides, the pharmacologically active metabolites, by several enzymes, including hypoxanthine guanine phosphoribosyltransferase.