Heterologous expression of xenobiotic mammalian-metabolizing enzymes in mutagenicity tester bacteria: an update and practical considerations.

There is an increasing need for metabolic competent cell systems for the mechanistic studies of biotransformation of xenobiotics in toxicology in general and in genotoxicology in particular. These cell systems combine the heterologous expression of a particular mammalian biotransformation enzyme with a specific target/ end point by which a functional analysis of the expressed gene product in the (geno)toxicity of chemicals can be performed. cDNAs of an increasing number of mammalian biotransformation enzymes is being cloned. The construction of specific expression vectors permits their heterologous expression in laboratory bacteria, such as Escherichia coli strains. This development does not only allow biochemical and enzymatic studies of (pure) enzyme preparations but also facilitates the engineering of metabolically competent mutagenicity tester bacteria, thereby providing new tools for genotoxicity testing and for studying of the roles of biotransformation in chemical carcinogenesis. In this review, we describe an update as well as an evaluation of enzymes expressed in mutagenicity tester bacteria. Four types of biotransformation enzymes are now expressed in these bacteria, namely, GSTs, CYPs, NATs, and STs. The expression of these enzymes in the tester bacteria and their subsequent application in mutagenicity assays demonstrates that heterologous expression in this type of bacteria has a number implications for the functionality of the biotransformation enzymes as well as for the functioning of the tester bacteria in mutagenicity detection. We also describe here a number of practical considerations in this regard.

Treatment of geriatric depression with trazodone, imipramine, and placebo: a double-blind study.

Sixty unipolar depressed geriatric outpatients were subjects in a double-blind study of a new antidepressant, trazodone, versus imipramine and placebo. Over the four week study, patients in the two active medication groups improved significantly compared to placebo on both observer and self-ratings. Although imipramine and trazodone had similar therapeutic efficacy, trazodone was judged to have fewer side effects than imipramine, suggesting that trazodone may have particular clinical utility in the geriatric population which is especially vulnerable to cardiovascular and anticholinergic side effects.