Carbon monoxide metabolite

The binding of sulfur and/or an activated intermediate of the phosphorus-containing portion of the parathion molecule to the endoplasmic reticulum leads to a decrease in the amount of cytochrome P-450 detectable as its carbon monoxide complex and to a decrease in the rate of metabolism of substrates such as benz-phetamine ( 19). Neither paraoxon nor any other isolatable metabolite of parathion decreases the amount of cytochrome P-450 or inhibits the ability of microsomes to metabolize substrates such a benzphetamine (19). 

Thus, exposure to any of these enzyme inducers concurrent with or after exposure to diazinon may result in accelerated bioactivation to the more potent anticholinesterase diazoxon. The extent of toxicity mediated by this phenomenon is dependent on how fast diazoxon is hydrolyzed to less toxic metabolites, a process that is also accelerated by the enzyme induction. Similarly, concurrent exposure to diazinon and MFO enzyme-inhibiting substances (e.g., carbon monoxide ethylisocyanide SKF 525A, halogenated alkanes, such as CC14 alkenes, such as vinyl chloride and allelic and acetylenic derivatives) may increase the toxicity of diazinon by decreasing the rate of the hydrolytic dealkylation and hydrolysis of both parent diazinon and activated diazinon (diazoxon) (Williams and Burson 1985). The balance between activation and detoxification determines the biological significance of these chemical interactions with diazinon. 

Andersen, M.E., Clewell, H.J., Gargas, M.L., MacNaughton, M.G., Reitz, R.H., Nolan, R.J. McKenna, M.J. (1991) Physiologically based pharmacokinetic modelling with dichloromethane, its metabolite, carbon monoxide, and blood carboxyhemoglobin in rats and humans. Toxicol, appl. Pharmacol.. 108, 14-27... 

Known metabolites of carbon tetrachloride include chloroform, carbon monoxide,... 

A particularly useful kind of biomarker used with increasing frequency during recent years consists of adducts of xenobiotics or their metabolites to biomolecules. A particularly straightforward example of such an adduct measured for many years as evidence of exposure is carboxyhe-moglobin, COHb, produced when inhaled carbon monoxide adds to blood hemoglobin, Hb ... 

CYP content (as measured spectrophotometrically at 450 nm in the presence of sodium dithionite and carbon monoxide) is usually reduced. Enzyme inactivation should be preceded by a catalytic event that converts the mechanism-based inhibitor to the inactivating metabolite. 

Most BEIs are defined as concentrations of determinants or biomarkers anticipated in biological specimens collected from healthy workers whose exposure to certain chemicals by all routes is equivalent to that of workers with inhalation only exposure at the OEL. Others measure reversible effects on the body, and still others are those that are below the concentrations associated with health effects. However, other definitions are common. For example, the German biological tolerance values (BAT) can be defined as rates of excretion of the chemical or its metabolites, or the maximum possible deviation from the norm of biological parameters induced by these substances in exposed humans. BEIs for some chemicals use other criteria, such as direct comparison with a measurable toxic effect, like carboxyhemoglobin in blood for carbon monoxide. 

Carbon tetrachloride is metabolized by cytochrome P-450 to the reactive metabolites trichloromethyl free radical and trichloromethylperoxy free radical. The trichloromethyl free radical may bind directly to cellular macromolecules such as lipids and proteins, and also to DNA, disrupting cell processes and breaking down membranes. The free radical can take part in anaerobic reactions, subsequently forming such toxic compounds as chloroform, hexachloroethane, and carbon monoxide. Aerobic biotransformation of the... 

The degradation of rutin by Aspergillus flavus proceeds by hydrolysis to the aglycone followed by degradation to a depside with release of the unusual metabolite carbon monoxide (Figure 4.51) and is accomplished by dioxygenation (Krishnamurty and Simpson 1970). 

Primary events. As already mentioned many compounds are toxic following metabolism to reactive metabolites. These reactive metabolites may then initiate one or more primary events. For example, paracetamol and bromobenzene-induced liver damage results from metabolic activation, discussed in more detail in Chapter 7. In other cases metabolic activation is not necessary, and the parent compound or a stable metabolite initiates the primary event. For example, cyanide is cytotoxic as a result of inhibition of crucial enzymes and carbon monoxide deprives the cell of oxygen (see Chapter 7 for more details). 

---