Thiopurine Use During Pregnancy Has Deleterious Effects on Offspring in Nudt15R138C Knock-In Mice

Imai, Toshio; Kawahara, Masahiro; Tatsumi, Goichi; Yamashita, Noriaki; Nishishita-Asai, Ai; Inatomi, Osamu; Masamune, Atsushi; Kakuta, Yoichi; Andoh, Akira

doi:10.1016/j.jcmgh.2021.03.006

Cited by 3 publications

(5 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…From the couple of heterozygous male mice and heterozygous female mice with 6-MP treatment (0.2 mg/kg or higher dose), no homozygous Nudt15 R138C/R138C mice were born. On the14.5th day of pregnancy, 6-MP (0.2 mg/kg) administration to the mother reduced the number of living homozygous fetal mice, and there was no living homozygous fetus in the mother treated with 6-MP (0.5 mg/kg) [27]. These findings indicated that thiopurine use during pregnancy leads to a lethal outcome for the fetus harboring the homozygous risk allele.…”

Section: Lessons From Nudt15 R138c Knock-in Micementioning

confidence: 85%

“…To clarify these points, we orally administered 6-MP at clinical dose to heterozygous Nudt15 ?/R138C or wild type Nudt15 ?/? pregnant mice [27] (Fig. 3).…”

Section: Lessons From Nudt15 R138c Knock-in Micementioning

confidence: 94%

“…The fetal mice with homozygous risk allele that survived under the mothers' 6-MP treatment tended to be pale and were significantly smaller in size than wild-type mice. Furthermore, the wild-type of female mice with a relatively higher-dose 6-MP treatment (1.0 mg/kg) were coupled with heterozygous male mice, and there was no newborn of heterozygous mice [27]. The number of hematopoietic stem cells was reduced in the fetus harboring Nudt15 risk allele.…”

Section: Lessons From Nudt15 R138c Knock-in Micementioning

confidence: 99%

“…However, this issue is ethically difficult to confirm in patients and there are no previous reports. Based on the findings in recently developed Nudt15 R138C knock-in mice [27,28], it may be necessary to know the NUDT15 genotype of not only women with IBD who are contemplating pregnancy but also their partner to avoid possible adverse outcomes in their offspring prior to thiopurine initiation.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Thiopurine pharmacogenomics and pregnancy in inflammatory bowel disease

et al. 2021

View full text Add to dashboard Cite

The thiopurine drugs azathioprine and 6-mercaptopurine are widely used for the maintenance of clinical remission in steroid-dependent inflammatory bowel disease (IBD). Thiopurines are recommended to be continued throughout pregnancy in IBD patients, but conclusive safety data in pregnant patients remain still insufficient. On the other hand, a strong association between a genetic variant of nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15 p.Arg139Cys) and thiopurine-induced myelotoxicity has been identified. Pharmacokinetic studies have revealed that thiopurine metabolism is altered in pregnant IBD patients and suggested that the fetus may be exposed to the active-thiopurine metabolite, 6-thioguaninetriphosphate, in the uterus. A recent study using knockin mice harboring the p.Arg138Cys mutation which corresponds to human p.Arg139Cys showed that oral administration of 6-MP at clinical dose induces a severe toxic effect on the fetus harboring the homozygous or heterozygous risk allele. This suggests that NUDT15 genotyping may be required in both women with IBD who are planning pregnancy (or pregnant) and their partner to avoid adverse outcomes for their infant. The risk to the fetus due to maternal thiopurine use is minimal but there are some concerns that are yet to be clarified. In particular, a pharmacogenomic approach to the fetus is considered necessary.

show abstract

Section: Lessons From Nudt15 R138c Knock-in Micementioning

confidence: 85%

“…To clarify these points, we orally administered 6-MP at clinical dose to heterozygous Nudt15 ?/R138C or wild type Nudt15 ?/? pregnant mice [27] (Fig. 3).…”

Section: Lessons From Nudt15 R138c Knock-in Micementioning

confidence: 94%

Section: Lessons From Nudt15 R138c Knock-in Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Thiopurine pharmacogenomics and pregnancy in inflammatory bowel disease

et al. 2021

View full text Add to dashboard Cite

show abstract

“…It also provides essential evidence for genotype-based prescribing, paving the way for personalized treatment strategies. Recently, concerns have been raised that this NUDT15 genotype may be associated with a fetal risk from maternal thiopurine administration during pregnancy, and this genetic test may be useful for assuaging such concerns, and in various other situations [ 31 , 32 ]. Future research should explore long-term treatment efficacy, the test’s utility in various diseases, and its role in determining treatment strategies based on test results.…”

Section: Discussionmentioning

confidence: 99%

Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study

Makuuchi,

Kakuta,

Umeno

et al. 2024

J Gastroenterol

View full text Add to dashboard Cite

Background This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies. Methods A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status. Results Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users. Conclusions NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

show abstract