Indirect-acting chemicals

Darroudi, F. Natarajan, A.T (1985) Cytostatie drug activity in plasma, a bioassay for detecting mutagenicity of directly and indirectly acting chemicals, an evaluation of 20 ohemieals. Mutat. Res., 143, 263-269... 

The actions of acetylcholine released from autonomic and somatic motor nerves are terminated by enzymatic hydrolysis of the molecule. Hydrolysis is accomplished by the action of acetylcholinesterase, which is present in high concentrations in cholinergic synapses. The indirect-acting cholinomimetics have their primary effect at the active site of this enzyme, although some also have direct actions at nicotinic receptors. The chief differences between members of the group are chemical and pharmacokinetic—their pharmacodynamic properties are almost identical. 

Darroudi, F., Meijers, C.M., Hadjidekova, V. Natarajan, A.T. (1996) Detection of aneugenic and clastogenic potential of X-rays, directly and indirectly acting chemicals in human hepatoma (Hep G2) and peripheral blood lymphocytes, using the mieronueleus assay and fluorescent in situ hybridization with a DNA centromeric probe. Mutagenesis, 11, 425-433... 

Indirect-Acting Defense Chemicals — Fatty Acid Inhibitors and Signal Transduction... 

In contrast, indirect-acting carcinogens generally are unre-active, water-insoluble compounds that can act as potent cancer inducers only after the Introduction of electrophlUc centers. In animals, cytochrome P 450 enzymes localized to the endoplasmic reticulum of liver cells normally function to add electrophilic centers to nonpolar foreign chemicals, such as certain insecticides and therapeutic drugs. In order to solubilize them so that they can be excreted from the body. But P-450 enzymes also can turn otherwise harmless chemicals Into carcinogens. 

A. Classification and Prototypes The indirect-acting cholinomimetic drugs fall into two major chemical classes carbamic acid esters (carbamates neostigmine is a prototype) and phosphoric acid esters (phosphates, organophosphates echothiophate is a prototype). A third class has only one member edrophonium is an alcohol (not an ester) with a very short duration of action. 

There is an important class of chemicals for which assessment of exposure times is even more complicated. Indirect-acting chemicals are not themselves active and must be metabolized to more active intermediates. Some cultured cells are better able to metabolize these chemicals than others e.g., benzo[a]pyrene induces more SCEs in cultured lymphocytes than in cultured CHO cells, provided the duration of exposure is at least 24 hr. Craig-Holmes and Shaw(23) suggested that in lymphocytes, benzo [a] pyrene induces the enzyme aryl hydrocarbon hydroxylase necessary for its own metabolism and that this induction and metabolism are brought about only if the cells are exposed to the chemical for at least 24 hr. If this is also true for SCE induction by other indirect-acting chemicals in cell types capable of metabolism, a long duration of exposure is necessary unless some other form of enzyme induction is used. 

The number of SCEs induced by direct-acting, stable chemicals such as MMC increases with the duration of exposure, but the effective length of treatment with unstable or indirect-acting chemicals is difficult to assess. In experiments using S-9 Mix, chemical exposures are necessarily short because the serum concentration must be very low during treatment for effective activation and because the enzymes in the S-9 Mix are unstable. Hence, the effective exposure to the active metabolite is brief and the metabolite itself may, in any case, be short-lived. Some chemicals, however, require an extended period of incubation with S-9 Mix e.g., acetylaminofluorene induced a twofold increase in SCE frequency after a 2.5-hr treatment with S-9, but no increase after the usual 30-min treatment. 

The SCE-inducing effect of several indirect-acting chemicals has been compared in three cell types with differing metabolizing capacityBHK... 

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