Phenotype:TPMT normal metabolizer

A TPMT normal metabolizer (NM) is a person who carries two normal-function TPMT alleles and therefore has the typical, reference level of thiopurine S-methyltransferase activity. It is one of the three metabolizer phenotypes assigned from TPMT genotype, above the poor metabolizer and intermediate metabolizer. TPMT has no rapid or ultrarapid phenotype, so the normal metabolizer is the highest-activity phenotype on the scale. This page describes the normal-metabolizer phenotype; the enzyme itself is covered at Enzyme:TPMT.

The normal metabolizer is the reference phenotype, and the standard doses of the thiopurine medicines were established in, and are calibrated to, normal-metabolizer patients. For a TPMT normal metabolizer, TPMT genotype is not a reason to depart from standard thiopurine dosing.

Genotype basis

The normal-metabolizer phenotype is produced by the \*1/\*1 diplotype, two normal-function alleles. The full allele catalogue is described on the Enzyme:TPMT page.

Population frequency

The TPMT normal-metabolizer phenotype is the great majority phenotype, found in roughly 86 to 97% of most populations. The large majority of patients prescribed a thiopurine are normal metabolizers, which is why standard thiopurine dosing works for most people, and why the poor metabolizer, at roughly 1 in 300, is a rare but genuinely dangerous exception worth testing for.

Clinical significance

For a TPMT normal metabolizer, standard dosing of azathioprine, mercaptopurine, and thioguanine applies, and TPMT genotype gives no reason to reduce the starting dose.

One caveat is especially important for this gene. A normal TPMT result does not clear a patient for standard thiopurine dosing on its own, because the parallel gene NUDT15 produces the same thiopurine-myelosuppression phenotype by a different mechanism, and NUDT15 loss-of-function is common in exactly the populations where TPMT loss-of-function is rare. A patient who is a TPMT normal metabolizer may still be a NUDT15 poor or intermediate metabolizer, and standard practice is to test both genes. A normal TPMT result is reassurance about one of the two thiopurine-safety genes, not both.

Standard thiopurine monitoring with periodic blood counts remains appropriate in a normal metabolizer, because non-genetic factors, including the allopurinol interaction, can still produce thiopurine toxicity.

See also

• Enzyme:TPMT, the enzyme, its history, and the inverted-logic explanation in full.
• Phenotype:TPMT poor metabolizer, Phenotype:TPMT intermediate metabolizer, the sibling phenotypes.
• Enzyme:NUDT15, the parallel thiopurine-safety gene that a normal TPMT result does not cover.
• Azathioprine, Mercaptopurine, Thioguanine (the entire clinical TPMT substrate set).
• Category:Pharmacogenomic phenotypes