Abstract. In TSH-secreting pituitary adenomas (TSHoma), octreotide (OCT) therapy reduces tumor size and TSH secretion in some cases but not in others. As OCT acts through various types of somatostatin receptors (SSTRs), the different responses of TSHoma to OCT might be explained by the differences of SSTR expression. We therefore studied the expression of subtype-specific SSTR mRNA transcripts in tumor tissues by RT-PCR. Type 2 (SSTR2) mRNA transcripts were detected in all 8 tumors but those of SSTR3 and SSTR5 were demonstrated only in 5 of them. Serum TSH levels were decreased by OCT administration test in all patients but OCT therapy was effective in two patients out of three. SSTR5 mRNA was detected in two tumors from the responder, but not in one tumor that was resistant to OCT. These observations suggest that the temporal decrease of TSH by OCT may be mediated by SSTR2, and that the long term response to OCT therapy may be related with the expression of SSTR5. Therefore, the expression of SSTR5 in TSHoma may be a useful marker for predicting the outcome of the therapy, but further studies with larger numbers of patients are necessary.

The cytochrome P450 enzymes MycCI and MycG are encoded within the mycinamicin biosynthetic gene cluster and are involved in the biosynthesis of mycinamicin II (a 16-membered macrolide antibiotic produced by Micromonospora griseorubida). Based on recent enzymatic studies, MycCI is characterized as the C-21 methyl hydroxylase of mycinamicin VIII, while MycG is designated multifunctional P450, which catalyzes hydroxylation and also epoxidation at C-14 and C-12/13 on the macrolactone ring of mycinamicin. Here, we confirm the functions of MycCI and MycG in M. griseorubida. Protomycinolide IV and mycinamicin VIII accumulated in the culture broth of the mycCI disruption mutant; moreover, the mycCI gene fragment complemented the production of mycinamicin I and mycinamicin II, which are produced as major mycinamicins by the wild strain M. griseorubida A11725. The mycG disruption mutant did not produce mycinamicin I and mycinamicin II; however, mycinamicin IV accumulated in the culture broth. The mycG gene was located immediately downstream of the self-resistance gene myrB. The mycG gene under the control of mycGp complemented the production of mycinamicin I and mycinamicin II. Furthermore, the amount of mycinamicin II produced by the strain complemented with the mycG gene under the control of myrBp was approximately 2-fold higher than that produced by the wild strain. In M. griseorubida, MycG recognized mycinamicin IV, mycinamicin V, and also mycinamicin III as the substrates. Moreover, it catalyzed hydroxylation and also epoxidation at C-14 and C-12/13 on these intermediates. However, C-14 on mycinamicin I was not hydroxylated. The cytochrome P450 enzymes (P450s) form a very large family of oxidative heme proteins, which are responsible for a diverse range of oxidative transformations across most life forms (12, 13). These reactions typically involve the modification of physiological and xenobiotic compounds and include the biosynthesis of various bioactive compounds (e.g., steroids, antibiotics, and signaling molecules). Approximately 40% of all known bacterial P450s are found in various species of the industrially important genus Streptomyces, which is the largest genus of the actinomycetes. Recent genome sequencing of the actinomycetes, particularly Streptomyces, has revealed an unexpectedly large number of genes encoding P450s (9,16,18,24,25). In secondary metabolic pathways, P450 genes are typically integrated within the biosynthetic cluster, where their products catalyze regiospecific and stereospecific oxidation of precursors. This results in structural diversity and also improved bioactivities of these molecules (21, 27). The P450s EryF (2) and EryK (30) are encoded within the erythromycin biosynthetic gene cluster and are involved in the biosynthesis of erythromycin A. Specifically, EryF catalyzes the hydroxylation of the macrolactone precursor 6-deoxyerthronolide B, while EryK catalyzes the formation of erythromycin D. As prototypic P450 hydroxylases involved in secondary metabolism, EryF and EryK exhibit stri...

Summary:  Purpose: This study attempted to clarify the role of histamine or histamine H1 receptors in the development of amygdaloid kindling by using histidine decarboxylase (HDC)‐deficient and histamine H1 receptor (H1R)‐deficient mice. Methods: Under pentobarbital anesthesia, mice were fixed to a stereotaxic apparatus, and bipolar electrodes were implanted into the right amygdala. Electrodes were connected to a miniature receptacle, which was embedded in the skull with dental cement. A bipolar electroencephalogram was recorded; bipolar stimulation of the amygdala was applied every day with a constant‐current stimulator and continued until a generalized convulsion was obtained. Results: The development of amygdaloid kindling in HDC‐deficient and H1R‐deficient mice was significantly accelerated compared with that in their respective wild‐type mice. In addition, the afterdischarge (AD) duration and generalized seizure duration in HDC‐deficient and H1R‐deficient mice were prolonged. Intraperitoneal injection of histidine resulted in an inhibition of amygdaloid kindled seizures in wild‐type mice at doses that caused an increase in the histamine contents of the brain. However, no significant effect was observed with histidine in H1R‐deficient mice at the same dose. Conclusions: These findings suggest that histaminergic mechanisms through H1 receptors play a crucial role not only in amygdaloid kindled seizures but also in the development of amygdaloid kindling.

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