Drug Metabolizing Systems

One general disadvantage of cell and tissue culture systems is their limited drug-metabolizing capacity, although drug-metabolizing cells or subcellular systems can be added to cultures in order to overcome this problem. An example is when hepatocytes rapidly lose their metabolic capacity. The following approaches have been used successfully used to improve the drug-metabolizing capacity of in-vitro systems:

• Active liver microsomal fractions from the rat, such as the standard "S-9 mix" used in the Ames' test.

• Freshly isolated hepatocytes from humans and other mammalian species.

• Co-cultures of hepatocytes and supporting liver cells essential to metabolize xenobiotics, such as bile duct epithelia.

• Hepatoma cell lines.

• Transgenic permanent cell lines expressing specific isoenzymes of human cytochrome P-450.

In addition, ex-vivo metabolites from exposed patients or animals can be added to cultures. Since transgenic cells do not contain the same set of regulating genes as, for example, human liver cells, the expression of human cytochrome P-450 in transgenic cells may be regulated differently. A more general disadvantage of the use of metabolizing systems is the lack of standardization among laboratories.

Although in-vitro systems can only be used to a limited extent in toxicity testing, they clearly offer a range of benefits (see Section 10.3).

Two aspects are especially important: first, due to their limitations, in-vitro systems allow attention to be focused on specific mechanisms, while second, studies can be conducted on human cells and tissues. In this way the toxicity of highly toxic chemicals (e.g., TCDD and dioxins) can be conducted on human cells, tissues and organs, without any ethical considerations.

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