Selectivity of imidazole-dioxolane compounds for in vitro inhibition of microsomal haem oxygenase isoforms.
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.
Kinobe
Robert T
RT
Department of Pharmacology & Toxicology, Queen's University, Botterell Hall 521, Kingston, ON, Canada K7L 3N6.
Vlahakis
Jason Z
JZ
Vreman
Hendrik J
HJ
Stevenson
David K
DK
Brien
James F
JF
Szarek
Walter A
WA
Nakatsu
Kanji
K
D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004148:Dioxolanes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008861:Microsomes / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004148:Dioxolanes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D019001:Nitric Oxide Synthase; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D006162:Guanylate Cyclase