Imrie P R, Marley E, Thomas D V
Br J Pharmacol. 1978 Sep;64(1):109-22. doi: 10.1111/j.1476-5381.1978.tb08647.x.
1 The metabolism and disposition in blood and tissues of exogenous [(14)C]-histamine was examined in cats.2 The principal metabolites in blood of histamine instilled into the small intestine (directly or by transfer from the stomach) and colon were imidazoleacetic acid and t-methylimidazoleacetic acid, being present in approximately equal amounts although in individual cats one or other acid could predominate. Only small amounts of histamine entered the circulation although in two of four cats given the largest dose (82 mumol/kg) large amounts were recovered. The amount of (14)C radioactivity absorbed varied directly with the dose instilled. The chief metabolite in kidney and urine, whether histamine was instilled into the intestine or infused parenterally, was t-methylimidazoleacetic acid. Histamine was not absorbed from the stomach and its metabolism there was negligible.3 In contrast, when histamine was infused into blood leaving the intestine (portal vein) the main metabolite in blood and tissues was t-methylimidazoleacetic acid being found in approximately 5-fold the concentration of imidazoleacetic acid. The small amount of histamine which eluded inactivation/uptake by liver, lungs, heart during the infusion was halved on circulation through the intestine. When histamine was infused into blood supplying the intestine, (cranial mesenteric artery) t-methylimidazoleacetic acid while still the major metabolite in blood was now only 1.4 times the concentration of imidazoleacetic acid. Additionally, the blood concentration of histamine during the infusion exceeded that of the metabolites.4t-Methylimidazoleacetic acid was also the principal metabolite in blood and tissues following histamine infusion into a cannula carrying a replacement venous blood supply to the liver of abdominally eviscerated cats. Imidazoleacetic acid and t-methylhistamine were present in equal concentrations and in one-quarter to one-third that of the methylated acid. The latter was also the principal metabolite following intra-arterial histamine infusion to abdominally eviscerated cats without a hepatic blood supply, although initially t-methylhistamine predominated: a large peak of histamine was present during the infusion period. When additionally the renal vessels were ligated, t-methylhistamine predominated throughout the experiment.5 In conclusion, intraduodenally instilled histamine was metabolized equally by diamine oxidase and imidazole N-methyltransferase (followed by deamination by monoamine oxidase). In contrast, imidazole N-methyltransferase was the principal inactivator of parenterally infused histamine, deamination of t-methylhistamine by monoamine oxidase becoming progressively less efficient with the cumulative exclusion of the intestines, liver and kidney from the circulation.
研究了外源[(14)C] - 组胺在猫体内血液和组织中的代谢及分布情况。
注入小肠(直接注入或经胃转运)和结肠的组胺在血液中的主要代谢产物是咪唑乙酸和t - 甲基咪唑乙酸,二者含量大致相等,不过在个别猫中,其中一种酸可能占主导。尽管在给予最大剂量(82 μmol/kg)的四只猫中有两只回收了大量组胺,但只有少量组胺进入循环系统。吸收的(14)C放射性量与注入剂量直接相关。无论组胺是注入肠道还是经肠胃外注入,肾脏和尿液中的主要代谢产物都是t - 甲基咪唑乙酸。组胺不会从胃中吸收,其在胃中的代谢可忽略不计。
相比之下,当将组胺注入离开肠道的血液(门静脉)时,血液和组织中的主要代谢产物是t - 甲基咪唑乙酸,其浓度约为咪唑乙酸的5倍。在注入过程中,少量未被肝脏、肺、心脏灭活/摄取的组胺在流经肠道后浓度减半。当将组胺注入供应肠道的血液(肠系膜前动脉)时,t - 甲基咪唑乙酸仍是血液中的主要代谢产物,但此时其浓度仅为咪唑乙酸的1.4倍。此外,注入过程中组胺的血液浓度超过了代谢产物的浓度。
在向腹部去脏猫的肝脏提供替代静脉血供应的插管中注入组胺后,t - 甲基咪唑乙酸也是血液和组织中的主要代谢产物。咪唑乙酸和t - 甲基组胺浓度相等,为甲基化酸浓度的四分之一至三分之一。在向没有肝脏血液供应的腹部去脏猫进行动脉内注入组胺后,后者也是主要代谢产物,尽管最初t - 甲基组胺占主导:注入期间出现了一个大的组胺峰值。另外,当结扎肾血管时,整个实验过程中t - 甲基组胺占主导。
总之,十二指肠内注入的组胺由二胺氧化酶和咪唑N - 甲基转移酶同等代谢(随后由单胺氧化酶脱氨基)。相比之下,咪唑N - 甲基转移酶是肠胃外注入组胺的主要灭活剂,随着肠道、肝脏和肾脏逐渐被排除在循环之外,单胺氧化酶对t - 甲基组胺的脱氨基作用效率逐渐降低。