Disease relevance of IPOMEANOL

• 4-Ipomeanol: a novel investigational new drug for lung cancer [1].
• Metabolic activation of 4-ipomeanol in human lung, primary pulmonary carcinomas, and established human pulmonary carcinoma cell lines [2].
• P-450-mediated activation of 4-ipomeanol to DNA binding metabolites was evaluated using a vaccinia virus complementary DNA expression system and an in situ DNA-binding assay [3].
• It is concluded that the endothelium lining capillaries and small veins, in addition to the nonciliated bronchiolar epithelial cell, are early targets in the development of 4-ipomeanol toxicity in the mouse and that the endothelial cell injury plays a major role in the development of pulmonary edema in this species [4].
• 4-Ipomeanol-induced effects on Sendai viral pneumonia in mice [5].

High impact information on IPOMEANOL

• 4-Ipomeanol (IPO) is a pulmonary-specific toxin that is metabolically activated by a cytochrome P450 pathway in lung tissue [2].
• CYP2F1 and CYP4B1, two enzymes that are expressed in lung, display only modest 3- and 2-fold respective increased abilities to metabolically activate 4-ipomeanol [3].
• Metabolic activation of 4-ipomeanol by complementary DNA-expressed human cytochromes P-450: evidence for species-specific metabolism [3].
• The activation pathway was concentration (4-ipomeanol) and time dependent and followed Michaelis-Menten kinetics [6].
• Weanling male CD-1 mice received 47 mg 4-ipomeanol/kg body weight by intraperitoneal injection and were studied at intervals from 2 to 360 hours after treatment [4].

Chemical compound and disease context of IPOMEANOL

• Effects of phenobarbital and 3-methylcholanthrene on the in vivo distribution, metabolism and covalent binding of 4-ipomeanol in the rat; implications for target organ toxicity [7].
• Diethylmaleate (DEM), an agent which depletes tissue glutathione (GSH), increased the covalent binding and toxicity of 4-ipomeanol [1-(3-furyl)-4-hydroxypentanone] in rats [8].
• Male Holstein calves were injected with either 4-ipomeanol (3 mg/kg) or vehicle (polyethylene glycol) 3 days prior to intratracheal inoculation with either parainfluenza virus or sham inoculum of culture medium [9].
• Lungs perfused with 4-ipomeanol and ventilated with air or 7.5% CO/20% O2 both displayed alveolar type II cell hyperplasia and alveolar macrophage infiltration [10].

Biological context of IPOMEANOL

• The morphogenesis of pulmonary edema and bronchiolar injury induced by the toxic furan, 4-ipomeanol, was studied by combined light and transmission electron microscopy [4].
• In vivo studies on the relationship between target organ alkylation and the pulmonary toxicity of a chemically reactive metabolite of 4-ipomeanol [11].
• At all time periods examined, DEM treatment produced no significant effect on the tissue distribution of unchanged 4-ipomeanol [8].
• As demonstrated recently, the novel prodrug activating gene coding for rabbit cytochrome P450 4B1 (CYP4B1) is able to induce tumor cell death at low micromolar concentrations in glioblastoma cells after treatment with the prodrug 4-ipomeanol (4-IM) in vitro and in vivo [12].
• This study establishes the impact of IPO cytotoxicity on 3 stages of rabbit Clara cell differentiation, early (2.5 and 5 days postnatal [DPN]), intermediate (7 and 9 DPN), and late (15 and 21 DPN), and relates the cytotoxicity to the extent of bronchiolar repair [13].

Anatomical context of IPOMEANOL

• The results further suggest the possibility that pulmonary endothelial cells have the capability of metabolizing xenobiotic compounds such as 4-ipomeanol to form ultimate toxins [4].
• Repeated intraperitoneal injections of 4-ipomeanol in rats resulted in extensive degeneration and necrosis of nonciliated (Clara) bronchiolar epithelial cells [14].
• Oral administration of carbon tetrachloride to rats or mice caused striking decreases in rat lung microsomal cytochrome P-450 and benzphetamine demethylase activity and in the enzyme-mediated covalent binding of 4-ipomeanol in preparations of rat and mouse lung microsomes, mouse lung slices and isolated whole-mouse lungs [15].
• Rat lung and liver microsomes mediated the biotransformation of the pulmonary toxin, 4-ipomeanol, to an alkylating metabolite [16].
• Effects of 4-ipomeanol on bovine alveolar macrophage function [17].

Associations of IPOMEANOL with other chemical compounds

• The in vitro metabolism and covalent binding of the furan derivative, 4-ipomeanol, was mediated by oxygen-requiring, NADPH-dependent, CO-inhibitable microsomal enzymes present in the livers, lungs and kidneys of adult male mice [18].
• Glutathione, catalase, and superoxide dismutase failed to protect P450 3A4 from inactivation by 4-ipomeanol [19].
• Metabolism of furans in vitro: ipomeanine and 4-ipomeanol [20].
• Comparison of ratios of covalent binding to total metabolism of the pulmonary toxin, 4-ipomeanol, in vitro in pulmonary and hepatic microsomes, and the effects of pretreatments with phenobarbital or 3-methylcholanthrene [21].
• Female Sprague-Dawley rats were given a single i.p. injection of arachis oil (n=20) or chemicals in arachis oil (n=10) that mainly damage Clara cells (4-ipomeanol (IPO) 8 mg x kg(-1) and methylcyclopentadienyl manganese tricarbonyl (MMT) 5 mg x kg(-1)) or endothelial cells (alpha-naphthylthiourea (ANTU) 5 mg x kg(-1)) [22].

Gene context of IPOMEANOL

• Mechanism-based inactivation of cytochrome P450 3A4 by 4-ipomeanol [19].
• The furanoterpenoid 4-ipomeanol (IPO) is a naturally occurring pneumotoxin which exerts its specific toxicity in Clara cells of the lung after activation by microsomal cytochrome P450 [23].
• Cytochrome P450 4B1 activity was assessed by the cytotoxicity of 4-ipomeanol, a known substrate for P450 4B1 and a model compound for chemical-induced injury to the lung [24].
• Phase II study of 4-ipomeanol, a naturally occurring alkylating furan, in patients with advanced hepatocellular carcinoma [25].

Analytical, diagnostic and therapeutic context of IPOMEANOL

• An analysis of tissue extracts by high-pressure liquid chromatography (HPLC) showed that both treatments markedly decreased the concentrations of unmetabolized 4-ipomeanol at all times examined [7].
• The importance of cytochrome P450 monooxygenase dependent metabolism in chemical-induced lung injury in animal models was established over 25 years ago with the furan, 4-ipomeanol [26].
• Significant elevations (P less than 0.05) in numbers of neutrophils and macrophages were recovered by bronchoalveolar lavage at times from 24 to 96 hours after 4-ipomeanol-treatment [27].
• This 4-ipomeanol-enhanced viral pneumonia was associated with significantly greater (P less than 0.05) numbers of pulmonary macrophages and neutrophils in the lavage fluid and higher (P less than 0.05) pulmonary titers of pulmonary infectious parainfluenza virus [9].
• Rats were given 3H-labelled 4-ipomeanol intravenously and whole-body autoradiography with freeze-dried sections, or with sections extracted with trichloroacetic acid, water and organic solvents, was performed to examine the disposition of unbound and bound radioactivity in various tissues [28].

References