Alkyl lead metabolism

Tetraethyl- and tetramethyl-lead do not themselves have toxic properties. The trialkyl compounds formed by dealkylation in the liver are the causes of toxic effects. A reduced toxicity of tetramethyl lead over tetraethyl lead is apparent because of the slower dealkylation rate of tetramethyl lead [73, 77]. 

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Organic Lead. Alkyl lead compounds are actively metabolized in the liver by oxidative dealkylation catalyzed by cytochrome P-450. 

Relatively few human studies that address the metabolism of alkyl lead compounds were found in the available literature. The dealkylation, mediated by cytochrome P-450, of alkyl lead compounds is thought to occur in the rat, mouse, and rabbit. This step converts tetraethyl and tetramethyl lead to the... 

Tetraethyl and tetramethyl lead under oxidative dealkylation metabolize to the highly neurotoxic metabolites, triethyl and trimethyl lead, respectively. In the liver, the reaction is catalyzed by a cytochrome P-450 dependent monoxygenase system (Kimmel et al. 1977). Complete oxidation of alkyl lead to inorganic lead also occurs (Bolanowska 1968). 

Decomposition of TAL in soil is also likely to be rapid in either sterile or non-sterile soils (half-life less than 1 day for TEL)." The products were partially alkylated lead compounds, which in turn decay or are metabolized by organisms. 

Urushibara, S., Experimental Studies on the Effect of Alkyl Lead in Leaded Gasoline on Cerebral Serotonin Metabolism, Tokyo Jikeikai Ika Daigaku Zasshi 91 [1976] 189/94. 

Cigarette smoke contains aryl hydrocarbons such as benzo[a]pyrene that, once metabolized to reactive compounds, can form alkyl adducts of DNA bases leading to mutations and cancers of the lung and many other organs. 

The alkylating agents can transfer an alkyl radical to a suitable receptor site. Alkylation of DNA within the nucleus represent the major interactions which will lead to cell death. These agents react chemically with sulfhydryl, carboxyl, amino and phosphate groups of other cellular nucleophiles in the cells which make them unavailable for the normal metabolic reactions. Alkylating agents react with nucleic acid and inhibit... 

Considerable work has been devoted to the search for agents devoid of the sedative effect that accompanied some of the earlier antihistamines. One stratagem for achieving that comprises adding a function that will diminish the likelihood that the dmg will cross the blood-brain barrier. The antistamine emedastine (41-3), for example, incorporates a terminal ether that can be potentially metabolized to a carboxylic acid. Alkylation of the imidazole (41-1), available from imidazol-2-one by reaction with phosphoms oxychloride, with the chloroether (41-2) leads to a reaction on nitrogen to afford (41-3). Displacement of the enol chloride in that intermediate with A-methyl-l-4-diazepine (41-4) leads to emedastine (41- 5) [43]. 

Fig. 10.9. Aminoacetamide lead series used in establishing thresholds for solubility and metabolic stability to guide the library design. R1 can be adamantyl, cycloalkyl, benzyl or substituted benzyl, aryl, or heteroaryl. R2 can be alkyl, substituted alkyl, cycloalkyl, benzyl, substituted benzyl, or acetyl. R3 can be FI or OFF...

Tamoxifen can undergo several routes of oxidative metabolism (Fig. 7.9). Thus, as expected aromatic hydroxylation to yield, the 4-hydroxy tamoxifen is catalyzed by cytochrome P-450. This metabolite is eliminated after conjugation. Alternatively, oxidation of the alkyl groups attached to the nitrogen atom, also catalyzed by cytochrome P-450, leads to dealkylation (Fig. 7.9). These are detoxication pathways. 

These studies have been extended by Pearson et al. (1993a,b), who showed that a number of metabolites contribute to protein binding in addition to 2-bromoacrolein. The major metabolic pathw ay leading to protein binding is C-2 oxidation of the 2,3-dibromo-propyl groups, giving a reactive a-bromoketone which might either alkylate proteins directly or be hydrolysed to bis(2,3,-dibromopropyl) phosphate and an a-bromo-a -hydroxyketone w hich could mediate the alkylation of protein. 

Vinylidene fluoride is taken up rapidly via the pulmonary route in rats, but at equilibrium the mean concentration (by volume) in rats was only 23% of that in the gaseous phase. Metabolism proceeded very slowly and was saturable at exposure concentrations of about 260 mg/m Its maximum rate was 1% that of vinyl chloride and less than 20% that of vinyl fluoride there has been a report of an increase in the urinary excretion of fluoride in exposed rats. No alkylating intermediate was demonstrated after passage through a mouse-liver microsomal system. However, vinylidene fluoride inhibits mixed-function oxidase activity in vitro and, like similar halogenated compounds that are transformed to reactive metabolites, it alters rat intermediary metabolism, leading to acetone exhalation (lARC, 1986). 

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