Metabolizing systems in short-term in vitro tests for carcinogenicity.

Area of Science:

• Toxicology
• Biochemistry
• Carcinogenesis

Background:

• Most mutagens require metabolic activation or inactivation.
• Lipophilic xenobiotics undergo metabolism, often involving cytochromes P-450, which can generate reactive intermediates.
• In vitro carcinogenicity tests often use exogenous metabolizing systems due to deficiencies in target cells.

Purpose of the Study:

• To investigate the role of metabolic activation and inactivation in mutagenicity.
• To evaluate the impact of different metabolizing systems on in vitro carcinogenicity test results.
• To determine which metabolizing systems best correlate with in vivo carcinogenicity.

Main Methods:

• Utilized various exogenous metabolizing systems: purified enzymes, crude subcellular preparations, intact cells (hepatocytes), and host animals.
• Compared results from tests using systems favoring activation versus those including inactivation pathways.
• Assessed the correlation between in vitro mutagenicity test outcomes and known carcinogenicity.

Main Results:

• Crude subcellular preparations, often used in short-term tests, tend to favor activating enzymes.
• Intact cells and host animals possess enzymes for both activation and inactivation, influencing outcomes.
• In vitro tests incorporating sufficient inactivating enzyme activity showed better correlation with carcinogenicity.

Conclusions:

• The choice of metabolizing system is critical in mutagenicity testing, especially for bacteria.
• Mammalian cells in culture retain significant inactivating enzyme activity.
• Providing adequate inactivating enzyme activity in in vitro mutagenicity assays enhances their predictive value for carcinogenicity.