Mixed Toxic metabolites

Exposure of various invertebrate species to high concentrations of petroleum did not induce mixed function oxidase activity. Enzyme activity was stimulated, however, in a number of fish tissues by petroleum. Different permutations can be addressed as to the significance of basal or induced levels of mixed function oxidases and hydrocarbon toxicity. AHH may have a physiological role in enhancing hydrocarbon clearance but may also increase the mutagenic-carcinogenic potential of hydrocarbons. Both of these concepts have been demonstrated in studies with fish (29,30). Induced AHH levels may permit a more rapid oxidative transformation with concomitant "disappearance" of parent hydrocarbons, but potentially toxic metabolites could be retained in tissues for longer periods (31). It is likely that at the enzymic level the... 

The mechanism of carbon tetrachloride hepatotoxicity generally is viewed as an example of lethal cleavage, where the CCh— Cl bond is split in the mixed-function oxidase system of the hepatocytes. After this cleavage damage may occur directly from the free radicals (-CCl and -Cl) and/or from the formation of toxic metabolites such as phosgene." ... 

The aversive agents diminish substance use by producing an aversive reaction when a specihc illicit substance is consumed. For example, disulfiram (Antabuse) prevents the breakdown of acetaldehyde, a toxic metabolite of alcohol, producing a noxious reaction when alcohol is consumed. While aversive agents have been in existence for decades, studies of their effectiveness in adults have produced mixed results (Kaminer, 1994b Garbutt et al., 1999). Likewise, there is only one published case report on the use of aversive therapy for pediatric SUD. Myers and associates (1994) reported on the use of disulfiram (Antabuse) for two teens with alcohol dependence. Both patients were briefly abstinent, but then became noncompliant and quickly relapsed. 

Renal tissue metabolism and transport mechanisms play important roles in the excretion and detoxification of xenobiotics (and/or their metabolites). Although the kidneys play an important part in the detoxification of xenobiotics, renal tissue may produce or increase the amounts of toxic metabolites received via the renal blood supply by metabolism (e.g., mixed-function oxidase reactions or concentrating effects within the nephron) (Piperno 1981 Commandeur and Vermeulen 1990 Goldstein 1994 Diamond and Zalups 1998 Endou 1998 Tarloff and Lash 2004). 

Phase I metabolism Phase I reactions (mainly oxidation, reduction, and hydrolysis) act as a preparation of the drug for the phase II reactions, i.e., a chemically reactive group is produced or uncovered on which the phase II reactions can occur, e.g., -OH, -NH2, -SH, -COOH. Most toxic metabolites are produced by phase I reactions. The P-450 isoenzymes (CYP enzymes), known collectively as the mixed function oxidase system, are found in the endoplasmic reticulum of many cells (notably those of liver, kidney, lung, and intestine) and perform many of these different functionalization reactions. The system requires the presence of molecular oxygen and co-factor nicotinamide adenine dinucleotide phosphate (NADPH) as well as cytochrome P450, NADPH-cytochrome P450 reductase, and lipid. 

The toxic metabolites of pyrrolizidine alkaloids are pyrrole derivatives produced by hepatic mixed function oxidases. These derivatives are highly reactive alkylating agents, which may act by alkylating sulphydryl groups 242, 270). In order to form these toxic pyrrolic metabolites, the alkaloids must possess 1,2-unsaturation in the necine [as in (100)], and be esterified at C-9. Substitution at the a-position of the acid and esterification of the C-7 hydroxy-group both increase the toxicity of the alkaloid. 

Environmental agents that influence microsomal reactions will influence hexachloroethane toxicity. The production of tetrachloroethene as a metabolite is increased by agents like phenobarbital that induce certain cytochrome P-450 isozymes (Nastainczyk et al. 1982a Thompson et al. 1984). Exposure to food material or other xenobiotics that influence the availability of mixed function oxidase enzymes and/or cofactors will change the reaction rate and end products of hexachloroethane metabolism and thus influence its toxicity. 

In mammals the cytochrome P-U50 mediated monooxygenase or mixed function oxidase system involved in the elimination of lipophilic environmental contaminants and other foreign compounds, has been implicated in the carcinogen activation process. There are several distinct variants of cytochrome P-U50 in mammalian tissues and there may be more than one form of this ubiquitous cytochrome also in fish. The significance of this lies in the fact that different forms of cytochrome P-U50 result in different metabolite patterns, which in turn may reflect on the carcinogenicity or toxicity of compounds being metabolized. 

Liver injury is clinically defined as an increase of serum alanine amino transferase (ALT) levels of more than three times the upper limit of normal and a total bilirubin level of more than twice the upper limit of normal [4]. The clinical patterns of liver injury can be characterized as hepatocellular (with a predominant initial elevation of ALT), cholestatic (with an initial elevation of alkaline phosphatase) or mixed. The mechanisms of drug-induced hepatotoxicity include excessive generation of reactive metabolites, mitochondrial dysfunction, oxidative stress and inhibition of bile salt efflux protein [5]. Better understandings of these mechanisms in the past decades led to the development of assays and models suitable for studying such toxic mechanisms and for selecting better leads in the drug discovery stage. 

Since the formation of the ethyleniminium ion is crucial for the cytotoxic activity of the nitrogen mustards, it is not surprising that stable ethylenimine derivatives have antitumor activity. Thiophospho-ramide or thiotepa is the best known compound of this type that has been used clinically. Both thiotepa and its primary metabolite, triethylenephos-phoramide (TEPA), to which it is rapidly converted by hepatic mixed-function oxygenases form crosslinks with DNA. It is mainly used as an intravesicu-lar agent in bladder cancer. Thiotepa produces little toxicity other than myelosuppression. 

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