No abstract

Neuroactive steroids are naturally occurring metabolites of endogenous steroid hormones, which exert rapid and nongenomic effects on membrane-bound neurotransmitter receptors. Those synthesized in the brain, termed neurosteroids, are believed to alter neuronal excitability through interaction with specific neurotransmitter receptors.1) Of the neurosteroids, 3a,5a-tetrahydroprogesterone (3a,5a-THP) and 3a,5a-tetrahydrodeoxycorticosterone (3a,5a-THDOC) are the most potent and efficacious of known positive allosteric modulators of g-aminobutyric acid type A (GABA A ) receptors.1-3) Numerous animal studies have shown that 3a,5a-THP and 3a,5a-THDOC are synthesized from progesterone and deoxycorticosterone, respectively, through the respective intermediates, 5a-dihydroprogesterone (5a-DHP) and 5a-dihydrodeoxycorticosterone (5a-DHDOC).3,4) The two sequential enzymatic reactions are catalyzed by steroid 5a-reductase and cytosolic NADPH-dependent 3a-hydroxysteroid dehydrogenase (3a-HSD, EC 1.1.1.213). On the other hand, microsomal NAD ϩ -dependent 3a-HSD oxidizes the neurosteroids back to 5a-DHP and 5a-DHDOC, and is thought to be involved in the catabolism of the potent GABA A ergic steroids.In the human, four isoenzymes of cytosolic NADP(H)-dependent 3a-HSD, which share at least 83% amino acid sequence identity and belong to the aldo-keto reductase (AKR) family, 5) have been identified. According to the nomenclature for the AKR family, these are termed AKR1C1, AKR1C2, AKR1C3 and AKR1C4, which correspond to previously known 3(20)a-HSD or 20a-HSD, 6,7) type 3 3a-HSD, 8) type 2 3a-HSD 9,10) and type 1 3a-HSD, 10) respectively. The four isoenzymes have recently been demonstrated to exhibit broad substrate specificities for 3a-, 17b-and 20a-hydroxysteroids, 11) but the preferences for the respective types of steroid substrates are different among the isoenzymes, as AKR1C1 shows high 20a-HSD activity 6) and AKR1C3 has been shown to be identical to type 5 17b-HSD 12) and prostaglandin F synthase. 13,14) Analyses of mRNA species for AKR1C isoenzymes in human tissues have shown that the isoenzymes, except for liver-specific AKR1C4, are expressed ubiquitously. 7,[9][10][11][14][15][16][17] In human brain AKR1C1, AKR1C2 and AKR1C3 are highly expressed, 11,16) although the distribution and localization of the enzymes in the brain remain unknown. These findings have suggested not only the roles of AKR1C1-AKR1C3 in the synthesis of the 3a,5a-THP and 3a,5a-THDOC, but also a possibility that the isoenzymes convert the potent neurosteroids to weak neurosteroids, 3a,20a-dihydroxypregnanes, 2,3) by exhibiting their 20a-HSD activities. However, there is limited information on the substrate specificity of human AKR1C isoenzymes for the neurosteroids and their precursors. To address the roles of human AKR1C isoenzymes in the metabolism of the neurosteroids, kinetic constants for the steroids have been determined with homogeneous recombinant AKR1C1-AKR1C3. Furthermore, we have found that several benzodiazepines, which bind to the GABA A recep...

Japanese monkey liver contains multiple forms of dihydrodiol dehydrogenase with 3(20)alpha-hydroxysteroid dehydrogenase activity. Here we have purified the major and minor forms (DD1 and DD4) of the enzyme from Cynomolgus monkey liver, and isolated cDNA species for the two enzyme forms by reverse transcription-PCR. The cDNAs encoded proteins comprising of 323 amino acids, in which the sequence identity between DD1 and DD4 was 83%. The sequences deduced from the cDNAs for DD1 and DD4 perfectly matched the partial sequences of peptides derived from the respective enzymes. We also isolated the cDNAs for DD1 and DD4 of Japanese monkey liver, which had almost identical amino acid sequences with those of the respective enzymes of Cynomolgus monkey liver. The monkey DD1s and DD4s showed the highest sequence identity (94%) with AKR1C1 and AKR1C4, respectively, of four isoenzymes of human 3(20)alpha-hydroxysteroid dehydrogenase, which belongs to the aldo-keto reductase family. The substrate specificity and inhibitor sensitivity of the purified recombinant Cynomolgu monkey DD1 and Japanese monkey DD4 were also essentially identical to those of the recombinant AKR1C1 and AKR1C4, respectively, indicating that DD1 and DD4 are homologues of human AKR1C1 and AKR1C4, respectively. The mRNA for DD1 was detected only in liver, kidney, intestine and adrenal gland among Japanese monkey tissues, and that for DD4 was expressed in liver and kidney. These tissue distribution patterns differ from those of human AKR1C1 and AKR1C4, which are expressed ubiquitously and liver-specific, respectively. In addition, no mRNA for an enzyme corresponding to another isoenzyme (AKR1C2) of the human enzyme was detected in livers of the two monkey strains. The results suggest a difference in the metabolism of steroids and xenobiotics mediated by 3(20)alpha-hydroxysteroid dehydrogenase isoenzymes between monkeys and humans.

A 42-year-old man was diagnosed with cStage IIIb malignant melanoma and underwent resection. After interferon-beta therapy, 18-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) showed multiple lung metastases, and he received nivolumab (2 mg/kg) every 3 weeks, resulting in a total of 17 cycles. After treatment, 18F-FDG PET/CT showed a significant decrease in the size of the metastases, but he had a Grade 4 alanine aminotransferase (ALT) elevation. Liver histology revealed drug-induced liver damage. Therefore, we performed steroid half-pulse therapy followed by oral methylprednisolone, but his ALT level did not completely recover to the normal range even after five months. We herein report a case with specific, sustained liver injury induced by nivolumab as an immune-related adverse events.

Background: A blister-packaged drug might be useful to enhance the eradication of Helicobacter pylori. We investigated the effect of a blister-packaged drug for H. pylori eradication. Methods: We treated 1,758 patients with H. pylori infections and evaluated the successful eradication rate in patients who underwent first-line eradication between January 2013 and May 2018. Treatments included a conventional proton pump inhibitor (PPI) blister-packaged drug containing lansoprazole or rabeprazole with clarithromycin (CAM) and amoxicillin (AC), vonoprazan (VPZ) with CAM and AC in a separate tablet, or a VPZ blister-packaged drug (VONOSAP) containing VPZ with CAM and AC, with all drugs given twice daily for 7 days. Results: Finally, we evaluated 1,263 patients (conventional PPI: n = 644, VPZ: n = 326, and VONOSAP: n = 293). The overall successful eradication rates were 71.9% in the conventional PPI group, 90.2% in the VPZ group, and 92.2% in the VONOSAP group. There was a significantly lower eradication rate in the PPI group than in the VPZ and VO-NOSAP (p < 0.00001, p < 0.0001) groups, but there was no significant difference between the VPZ and VONOSAP groups (p = 0.4006). We enrolled a total of 256 age-and gender-matched patients in the VPZ and VONOSAP groups, and both groups had successful eradication rates of approximately 90% (89.8 vs. 90.4%, respectively, p = 0.7641). After analyzing the subgroup of patients older than 75 years, there was a significant treatment benefit of VONOSAP but not of VPZ in elderly patients (EPs). Conclusion: Triple-drug blisterpackaged drugs including VPZ may improve the first-line eradication of H. pylori in EPs.