Corticosteroid suppresses urea-cycle-related gene expressions in ornithine transcarbamylase deficiency
Abstract Background Ornithine transcarbamylase deficiency (OTCD) is most common among urea cycle disorders (UCDs), defined by defects in enzymes associated with ureagenesis. Corticosteroid administration to UCD patients, including OTCD patients, is suggested to be avoided, as it may induce life-thre...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-03-01
|
| Series: | BMC Gastroenterology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12876-022-02213-0 |
| _version_ | 1819052061595009024 |
|---|---|
| author | Koji Imoto Masatake Tanaka Takeshi Goya Tomomi Aoyagi Motoi Takahashi Miho Kurokawa Shigeki Tashiro Masaki Kato Motoyuki Kohjima Yoshihiro Ogawa |
| author_facet | Koji Imoto Masatake Tanaka Takeshi Goya Tomomi Aoyagi Motoi Takahashi Miho Kurokawa Shigeki Tashiro Masaki Kato Motoyuki Kohjima Yoshihiro Ogawa |
| author_sort | Koji Imoto |
| collection | DOAJ |
| description | Abstract Background Ornithine transcarbamylase deficiency (OTCD) is most common among urea cycle disorders (UCDs), defined by defects in enzymes associated with ureagenesis. Corticosteroid administration to UCD patients, including OTCD patients, is suggested to be avoided, as it may induce life-threatening hyperammonemia. The mechanism has been considered nitrogen overload due to the catabolic effect of corticosteroids; however, the pathophysiological process is unclear. Methods To elucidate the mechanism of hyperammonemia induced by corticosteroid administration in OTCD patients, we analyzed a mouse model by administering corticosteroids to OTCspf−ash mice deficient in the OTC gene. Dexamethasone (DEX; 20 mg/kg) was administered to the OTCspf−ash and wild-type (WT) mice at 0 and 24 h, and the serum ammonia concentrations, the levels of the hepatic metabolites, and the gene expressions related with ammonia metabolism in the livers and muscles were analyzed. Results The ammonia levels in Otcspf−ash mice that were administered DEX tended to increase at 24 h and increased significantly at 48 h. The metabolomic analysis showed that the levels of citrulline, arginine, and ornithine did not differ significantly between Otcspf−ash mice that were administered DEX and normal saline; however, the level of aspartate was increased drastically in Otcspf−ash mice owing to DEX administration (P < 0.01). Among the enzymes associated with the urea cycle, mRNA expressions of carbamoyl-phosphate synthase 1, ornithine transcarbamylase, arginosuccinate synthase 1, and arginosuccinate lyase in the livers were significantly downregulated by DEX administration in both the Otcspf−ash and WT mice (P < 0.01). Among the enzymes associated with catabolism, mRNA expression of Muscle RING-finger protein-1 in the muscles was significantly upregulated in the muscles of WT mice by DEX administration (P < 0.05). Conclusions We elucidated that corticosteroid administration induced hyperammonemia in Otcspf−ash mice by not only muscle catabolism but also suppressing urea-cycle-related gene expressions. Since the urea cycle intermediate amino acids, such as arginine, might not be effective because of the suppressed expression of urea-cycle-related genes by corticosteroid administration, we should consider an early intervention by renal replacement therapy in cases of UCD patients induced by corticosteroids to avoid brain injuries or fatal outcomes. |
| first_indexed | 2024-12-21T12:13:51Z |
| format | Article |
| id | doaj.art-128a89dde75a40a5b63bf49df7ae0500 |
| institution | Directory Open Access Journal |
| issn | 1471-230X |
| language | English |
| last_indexed | 2024-12-21T12:13:51Z |
| publishDate | 2022-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Gastroenterology |
| spelling | doaj.art-128a89dde75a40a5b63bf49df7ae05002022-12-21T19:04:29ZengBMCBMC Gastroenterology1471-230X2022-03-0122111110.1186/s12876-022-02213-0Corticosteroid suppresses urea-cycle-related gene expressions in ornithine transcarbamylase deficiencyKoji Imoto0Masatake Tanaka1Takeshi Goya2Tomomi Aoyagi3Motoi Takahashi4Miho Kurokawa5Shigeki Tashiro6Masaki Kato7Motoyuki Kohjima8Yoshihiro Ogawa9Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu UniversityAbstract Background Ornithine transcarbamylase deficiency (OTCD) is most common among urea cycle disorders (UCDs), defined by defects in enzymes associated with ureagenesis. Corticosteroid administration to UCD patients, including OTCD patients, is suggested to be avoided, as it may induce life-threatening hyperammonemia. The mechanism has been considered nitrogen overload due to the catabolic effect of corticosteroids; however, the pathophysiological process is unclear. Methods To elucidate the mechanism of hyperammonemia induced by corticosteroid administration in OTCD patients, we analyzed a mouse model by administering corticosteroids to OTCspf−ash mice deficient in the OTC gene. Dexamethasone (DEX; 20 mg/kg) was administered to the OTCspf−ash and wild-type (WT) mice at 0 and 24 h, and the serum ammonia concentrations, the levels of the hepatic metabolites, and the gene expressions related with ammonia metabolism in the livers and muscles were analyzed. Results The ammonia levels in Otcspf−ash mice that were administered DEX tended to increase at 24 h and increased significantly at 48 h. The metabolomic analysis showed that the levels of citrulline, arginine, and ornithine did not differ significantly between Otcspf−ash mice that were administered DEX and normal saline; however, the level of aspartate was increased drastically in Otcspf−ash mice owing to DEX administration (P < 0.01). Among the enzymes associated with the urea cycle, mRNA expressions of carbamoyl-phosphate synthase 1, ornithine transcarbamylase, arginosuccinate synthase 1, and arginosuccinate lyase in the livers were significantly downregulated by DEX administration in both the Otcspf−ash and WT mice (P < 0.01). Among the enzymes associated with catabolism, mRNA expression of Muscle RING-finger protein-1 in the muscles was significantly upregulated in the muscles of WT mice by DEX administration (P < 0.05). Conclusions We elucidated that corticosteroid administration induced hyperammonemia in Otcspf−ash mice by not only muscle catabolism but also suppressing urea-cycle-related gene expressions. Since the urea cycle intermediate amino acids, such as arginine, might not be effective because of the suppressed expression of urea-cycle-related genes by corticosteroid administration, we should consider an early intervention by renal replacement therapy in cases of UCD patients induced by corticosteroids to avoid brain injuries or fatal outcomes.https://doi.org/10.1186/s12876-022-02213-0Ornithine transcarbamylase deficiencyCorticosteroidHyperammonemiaUrea cycle disorderLate-onset ornithine transcarbamylase deficiency |
| spellingShingle | Koji Imoto Masatake Tanaka Takeshi Goya Tomomi Aoyagi Motoi Takahashi Miho Kurokawa Shigeki Tashiro Masaki Kato Motoyuki Kohjima Yoshihiro Ogawa Corticosteroid suppresses urea-cycle-related gene expressions in ornithine transcarbamylase deficiency BMC Gastroenterology Ornithine transcarbamylase deficiency Corticosteroid Hyperammonemia Urea cycle disorder Late-onset ornithine transcarbamylase deficiency |
| title | Corticosteroid suppresses urea-cycle-related gene expressions in ornithine transcarbamylase deficiency |
| title_full | Corticosteroid suppresses urea-cycle-related gene expressions in ornithine transcarbamylase deficiency |
| title_fullStr | Corticosteroid suppresses urea-cycle-related gene expressions in ornithine transcarbamylase deficiency |
| title_full_unstemmed | Corticosteroid suppresses urea-cycle-related gene expressions in ornithine transcarbamylase deficiency |
| title_short | Corticosteroid suppresses urea-cycle-related gene expressions in ornithine transcarbamylase deficiency |
| title_sort | corticosteroid suppresses urea cycle related gene expressions in ornithine transcarbamylase deficiency |
| topic | Ornithine transcarbamylase deficiency Corticosteroid Hyperammonemia Urea cycle disorder Late-onset ornithine transcarbamylase deficiency |
| url | https://doi.org/10.1186/s12876-022-02213-0 |
| work_keys_str_mv | AT kojiimoto corticosteroidsuppressesureacyclerelatedgeneexpressionsinornithinetranscarbamylasedeficiency AT masataketanaka corticosteroidsuppressesureacyclerelatedgeneexpressionsinornithinetranscarbamylasedeficiency AT takeshigoya corticosteroidsuppressesureacyclerelatedgeneexpressionsinornithinetranscarbamylasedeficiency AT tomomiaoyagi corticosteroidsuppressesureacyclerelatedgeneexpressionsinornithinetranscarbamylasedeficiency AT motoitakahashi corticosteroidsuppressesureacyclerelatedgeneexpressionsinornithinetranscarbamylasedeficiency AT mihokurokawa corticosteroidsuppressesureacyclerelatedgeneexpressionsinornithinetranscarbamylasedeficiency AT shigekitashiro corticosteroidsuppressesureacyclerelatedgeneexpressionsinornithinetranscarbamylasedeficiency AT masakikato corticosteroidsuppressesureacyclerelatedgeneexpressionsinornithinetranscarbamylasedeficiency AT motoyukikohjima corticosteroidsuppressesureacyclerelatedgeneexpressionsinornithinetranscarbamylasedeficiency AT yoshihiroogawa corticosteroidsuppressesureacyclerelatedgeneexpressionsinornithinetranscarbamylasedeficiency |