The long-term objectives of this project are to study the effects of a series of organic solvents on metabolism of the carcinogenic polyaromatic hydrocarbon, benzo(a)pyrene and evaluate the interaction between selected solvents and acute ethanol on BaP metabolism. As both the solvents under investigation and ethanol are lipophilic in nature and have been shown to alter membrane (i.e microsomal) integrity, we will study the effects of selected solvents and/or acute ethanol exposure on membrane composition (cholesterol, phospholipids, fatty acids) and function (fluidity) to determine their role in observed alterations in BaP metabolism. This project is part of an investigation on the metabolic basis of ethanol and xenobiotic interactions of toxicological significance. The concurrent exposures to organic solvents and ethanol in workers exposed to BaP through cigarette smoking is widespread. There is a strong correlation between cancer of the upper respiratory tract and drinking which is seen only in smokers. Ethanol and xylene increased metagenic BaP metabolites in liver and lung, respectively, but their interaction has not been tested in either lung or liver. In this research: 1) the metabolism in vitro of BaP will be measured in the lung and liver of rats administered: a) xylene and structural analogs of xylene, b) short chained aliphatic alcohols and aldehydes, and c) a series of halogenated aliphatic compounds. This will indicate the structural types involved in the BaP action in the lung. 2) the effects of concurrent ethanol administration with solvents action on BaP metabolism will be measured. This will indicate whether there are interactions between the solvents and ethanol as predicted from the literature. 3) the effects of solvent and/or ethanol exposure on membrane composition and function as well as tissue glutathionine (oxidized and reduced) will be measured. This will elucidate the mechanism(s) of solvent/alcohol interactions or xenobiotic (BaP) metabolism as they relate to altered membrane integrity and altered cellular glutathione content. 4) the effects of adrenalectomy will be measured for the exposure to solvents and for the concurrent solvent-ethanol exposures. This will indicate whether the permissive effect of the adrenals seen for the liver is also present in the lung.
| Furman, G M; Silverman, D M; Schatz, R A (1991) The effect of toluene on rat lung benzo[a]pyrene metabolism and microsomal membrane lipids. Toxicology 68:75-87 |
| Silverman, D M; Schatz, R A (1991) Pulmonary microsomal alterations following short-term low level inhalation of p-xylene in rats. Toxicology 65:271-81 |
| Stickney, J A; Silverman, D M; Schatz, R A (1991) Role of isozyme-specific inhibition of cytochrome P450IIB1 activity in m-xylene-induced alterations in rat pulmonary benzo(a)pyrene metabolism. Xenobiotica 21:641-9 |
| Stickney, J A; Roberts, A E; Silverman, D M et al. (1989) The effect of m-xylene on rat lung benzo[a]pyrene metabolism and microsomal membrane lipids: comparison with p-xylene. Toxicology 58:155-65 |
