Halogenated methanes: metabolism and toxicity.

Area of Science:

• Biochemistry
• Toxicology
• Drug Metabolism

Background:

• Dihalomethanes and haloforms undergo metabolic transformation in biological systems.
• Carbon monoxide (CO) is a known product of certain xenobiotic metabolisms.
• Hepatic microsomal enzymes, particularly cytochrome P-450, play a crucial role in xenobiotic detoxification.

Purpose of the Study:

• To elucidate the metabolic pathways of dihalomethanes and haloforms.
• To investigate the mechanism of carbon monoxide (CO) formation from these compounds.
• To identify key enzymes and intermediates involved in these metabolic processes.

Main Methods:

• In vivo and in vitro metabolic studies using radiolabeled compounds ([14C]dichloromethane).
• Enzymatic assays involving hepatic microsomes and cytosol fractions.
• Reaction mechanism studies to identify intermediates and catalysts.

Main Results:

• Dihalomethanes are metabolized to CO via a cytochrome P-450 dependent pathway involving formyl halide intermediates.
• [14C]dichloromethane forms covalent adducts with microsomal proteins and lipids.
• Dihalomethanes are also metabolized to formaldehyde and formic acid by glutathione transferase.
• Haloforms are metabolized to CO by cytochrome P-450, a reaction stimulated by sulfhydryl compounds, involving dihalocarbonyl intermediates.

Conclusions:

• A common formyl halide intermediate may be responsible for CO formation and covalent binding of dihalomethanes.
• Glutathione transferase is involved in the metabolism of dihalomethanes to formaldehyde and formic acid.
• Sulfhydryl compounds modulate haloform metabolism to CO, suggesting a distinct mechanism involving dihalocarbonyl intermediates.