Thiopurine Methyltransferase in Humans: Development and Tissue Distribution

Abstract

Thiopurine methyltransferase (EC 2.1.1.67, TPMT) was studied with 6-mercaptopurine as substrate in the cytosolic fraction from 18 human fetal liver, 16 placental and 22 adult liver specimens. TPMT activity (pmol × min^-1 × mg^-1; mean ± SD) was 33.2 ± 15.8 (fetal liver), 19.5 ± 11.1 (placenta) and 105 ± 57.1 (adult liver). Fetal liver activity of TPMT is one third that in adult liver suggesting that this enzyme is well developed in the midgestational human fetus. The distribution of TPMT seems to be ubiquitous both in the fetus and adult subject. The kidney is an important site of methylation as suggested by the renal activity of TPMT (197 ± 70 pmol × min^-1 × mg^-1) which is twice as high as the hepatic one. Fetal and adult hepatic TPMT obey nonmichaelian kinetics. Two phases, one with lower and one with higher affinity for 6-mercaptopurine, were observed. The average K(m) for the high affinity phase was 0.12 mmol/l (fetus) and 0.13 mmol/l (adult), whereas the K(m) for the lower affinity phase was 1.79 mmol/l (fetus) and 1.42 mmol/l (adult). This paper shows that TPMT develops before the second trimester of gestation in human fetus, that it has an ubiquitous distribution in the human fetus and adult subjects and the kinetic pattern of this enzyme is consistent in fetal and adult liver.

Conjugation of Benzoic Acid with Glycine in the Human Fetal and Adult Liver and Kidney

“…Our previous work on the development of conjugation pathways in humans has shown that the activities of the cytosolic enzymes, such as acetyl transferase [7], glutathione Stransferase [8], sulphotransferase(s) [9,10] and thiopurinemethyltransferase [11], are 2-3 times lower in fetal than adult liver. In con trast, the activities of uridine diphosphate glucuronyl transferase [12,13] and thiomethyltransferase [14] are 6-108 times lower in fetal than adult liver.…”

“…Our previous work on conjugation path ways has shown that some cytosolic enzymes such as acetyl transferase [7], glutathione Stransferase [8], sulphotransferase [9,10] and thiopurine methyltransferase [11] are better developed in fetal life compared to the pre dominantly microsomal enzymes such as glucuronyl transferase [12,13] and thiomethyltransferase [14], In order to ascertain whether such a differential development pat tern holds true for other non-microsomal enzymes as well, we measured the rate of for mation of hippuric acid from benzoic acid, which is believed to be catalysed by a mito chondrial enzyme system, namely glycine transferase [3][4][5]15], in human fetal and adult livers and kidney.…”

Thiol Methyltransferase in Humans: Development and Tissue Distribution

“…Therefore, the developmental pattern of TMT is tissuedependent and the adult kidney seems to be an important site of méthylation. Such a consideration holds true for thiopurinemethyltransferase, the activity of which is twice as high in kidney than in liver [13].…”

Thiopurines in Inflammatory Bowel Disease - The Role of Pharmacogenetics and Therapeutic Drug Monitoring

“…TPMT is a cytoplasmic enzyme present in liver, kidney and brain cells, red and white blood cells and bone marrow cells that catalyses the S-methylation of 6-MP and 6-TG [Remy 1967;Weinshilboum et al, 1978;Van Loon and Weinshilboum 1982;Woodson and Weinshilboum 1983;Weinshilboum 1989;Pacifici et al, 1991;Szumlanski et al, 1992;Van Loon et al, 1992;McLeod et al, 1995;Coulthard et al, 1998] with S-adenosyl methionine (SAM) as a methyl donor [Remy 1963;Elion 1967]. Although extensively studied and present already in primitive species [Otterness et al, 1985;Salavaggione et al, 2005], the physiological role of TPMT is not clear and a defective enzyme has not been linked to any disease .…”