Kinobe Robert T, Vlahakis Jason Z, Vreman Hendrik J, Stevenson David K, Brien James F, Szarek Walter A, Nakatsu Kanji
Department of Pharmacology & Toxicology, Queen's University, Botterell Hall 521, Kingston, ON, Canada K7L 3N6.
Br J Pharmacol. 2006 Feb;147(3):307-15. doi: 10.1038/sj.bjp.0706555.
Haem oxygenases (HO) are involved in the catalytic breakdown of haem to generate carbon monoxide (CO), iron and biliverdin. It is widely accepted that products of haem catabolism are involved in biological signaling in many physiological processes. Conclusions to most studies in this field have gained support from the judicious use of synthetic metalloporphyrins such as chromium mesoporphyrin (CrMP) to selectively inhibit HO. However, metalloporphyrins have also been found to inhibit other haem-dependent enzymes, such as nitric oxide synthase (NOS), cytochromes P-450 (CYPs) and soluble guanylyl cyclase (sGC), induce the expression of HO-1 or exhibit varied toxic effects. To obviate some of these problems, we have been examining non-porphyrin HO inhibitors and the present study describes imidazole-dioxolane compounds with high selectivity for inhibition of HO-1 (rat spleen microsomes) compared to HO-2 (rat brain microsomes) in vitro. (2R,4R)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-methyl-1,3-dioxolane hydrochloride) was identified as the most selective inhibitor with a concentration of 0.6 microM inhibiting HO-1(inducible) by 50% compared with 394 microM for HO-2 (constitutive). These compounds were found to have no effects on the catalytic activities of rat brain NOS and lung sGC, but were potent inhibitors of microsomal CYP2E1 and CYP3A1/3A2 activities. In conclusion, we have identified imidazole-dioxolanes that are able to inhibit microsomal HO in vitro with high selectivity for HO-1 compared to HO-2, and little or no effect on the activities of neuronal NOS and sGC. These molecules could be used to facilitate studies on the elucidation of physiological roles of HO/CO in biological systems.
血红素加氧酶（HO）参与血红素的催化分解，生成一氧化碳（CO）、铁和胆绿素。血红素分解代谢产物参与许多生理过程中的生物信号传导，这一点已被广泛接受。该领域大多数研究的结论都得到了明智使用合成金属卟啉（如中卟啉铬（CrMP））以选择性抑制HO的支持。然而，人们还发现金属卟啉会抑制其他血红素依赖性酶，如一氧化氮合酶（NOS）、细胞色素P - 450（CYPs）和可溶性鸟苷酸环化酶（sGC），诱导HO - 1的表达或表现出不同的毒性作用。为了避免其中一些问题，我们一直在研究非卟啉HO抑制剂，本研究描述了与体外HO - 2（大鼠脑微粒体）相比对HO - 1（大鼠脾微粒体）具有高选择性抑制作用的咪唑 - 二氧戊环化合物。（2R，4R）-2 - [2 - （4 - 氯苯基）乙基] - 2 - [（1H - 咪唑 - 1 - 基）甲基] - 4 - 甲基 - 1，3 - 二氧戊环盐酸盐被确定为最具选择性的抑制剂，浓度为0.6微摩尔时可抑制HO - 1（诱导型）50%，而抑制HO - 2（组成型）则需要394微摩尔。这些化合物对大鼠脑NOS和肺sGC的催化活性没有影响，但却是微粒体CYP2E1和CYP3A1/3A2活性的有效抑制剂。总之，我们已经鉴定出咪唑 - 二氧戊环类化合物，它们能够在体外以与HO - 2相比对HO - 1具有高选择性的方式抑制微粒体HO，并且对神经元NOS和sGC的活性几乎没有影响。这些分子可用于促进对HO/CO在生物系统中的生理作用的阐明研究。
