Metabolic activation of 4-ipomeanol in human lung, primary pulmonary carcinomas, and established human pulmonary carcinoma cell lines

4-Ipomeanol (IPO) is a pulmonary-specific toxin that is metabolically activated by a cytochrome P450 pathway in lungtissue. In this study, IPO metabolism, as determined by measurement of [¹⁴C]IPO covalent binding, was evaluated in a diverse sampling of 18 established, human lung cancer cell lines as well as in normal lung tissue and primary lung carcinoma tissue obtained at the time of thoracotomy from 56 patients with lung cancer. [¹⁴C]IPO covalent binding in lung cancer cell lines ranged from 248 to 1,047 pmol of bound [¹⁴C] IPO per milligram of protein per 30 minutes (mean ±SE =547 ± 62.2). IPO metabolism in normal lung tissue ranged from 12 to 2,007 pmol of covalently bound [¹⁴C]IPO per milligram of protein per 30 minutes (mean ±SE = 549 ± 60). In lung cancer tissue, values ranged from 0 to 2,566 pmol of covalently bound [¹⁴C]IPO per milligram of protein per 30 minutes (mean ± SE = 547 ± 60, > .3). When patients were divided into smokers and current nonsmokers (no tobacco products smoked for >6mo), no effects of cigarette smoking were observed for either normal lung tissue or lung tumor tissue (P > .1 in all instances). A wide range of IPO metabolic activity was observed among different histological classifications of lung cancer cell lines and of fresh lung cancer tissues. IPO metabolism was simultaneously compared in normal lungtissue and lung cancer tissue from individual patients, but no positive correltion was observed (r = .10; P>.30).The results clearly demonstrate a wide range of IPO metabolism in both normal and lung cancer cells and indicate that a wide diversity of human lung cancers possess the metabolic enzyme systms(s) necessary for the bioactivation of IPO to a potentially cytotoxic intermediate. Therefore, the continued exploration for any possible therapeutic potential of IPO in patients with lung cancer appears warranted. [J Natl Cancer Inst 82:1420-1426, 1990]