Inactivation of Rat Liver Cytochrome P-450 by the Suicide Substrates Parathion and Chloramphenicol

Inhibition of Cytochrome P450 Enzymes

“…14 C]-modified amino acid residue [299][300][301][302] Hydrolysis of the modified amino acid residue yielded lysine and a fragment of the chloramphenicol indicating that chloramphenicol was converted to an oxamyl chloride intermediate that then could either modify a critical lysine residue on the protein or be hydrolyzed to give the oxamic acid Acylation of the lysine residue is suggested to inhibit the transfer of electrons from CPR to CYP2B1, since the inactivated enzyme was still catalytically active in the presence of either iodosobenzene or cumene hydroperoxide [302] The observation that the 7-EFC activity is not inhibited at all by the presence of chloramphenicol when activated oxygen donors are used suggests that the chloramphenicol is not covalently bound in the substrate-binding site…”

“…A variety of functional groups that either occur naturally or have been specifically engineered into drugs to increase their stability, solubility, or bioavailability have been shown to predispose these drugs to metabolism by a particular P450 isozyme or isozymes in such a way as to generate reactive intermediates that can lead to MBI by one or more of the previously mentioned routes These molecules can be grouped according to their structural aspects and they fall into a number of major categories including: (a) various sulfur-containing compounds (eg, carbon disulfide [281][282][283], diethyldithiocarbamate [284], isothiocyanates [285], mercaptosteroids [286][287][288][289][290][291][292][293], parathion [294,295], thioureas [296], thiophenes [297], and tienilic acid [298]; (b) various halogen containing compounds such as chloramphenicol [299][300][301][302], N-monosubstituted dichloroacetamides [303], and N(2-p-nitrophenethyl) dichloroacetamide [304]; (c) acetylenes and alkyl and aryl olefins [305][306][307][308][309][310][311] [328][329][330][331][332][333][334][335][336], and the furanopyridine, L-75...…”

Stereochemistry of the Functional Group Determines the Mechanism of Aromatase Inhibition by 6-Bromoandrostenedione*

“…Other research groups have developed similar analogs, including the 10-propargyl and 10-allenyl derivatives of estr-4-ene-3,17-dione; the Ki and k inact values are 23 nM and 0.067 min" 1 for the former compound and 14 nM and 0.029 min" 1 for the latter (42,43). These compounds would be expected to be aromatase inhibitors in view of the known reactions of P-450 cytochromes (44,45); however, the inactivation by 6/3-BrA is not as readily explained. Norethisterone, 4-hydroxyandrostenedione, l,4,6-androstatriene-3,17-dione, testololactone, and 4-androstene-3,6,17-trione have also been reported to be suicide-type inhibitors (28,(46)(47)(48).…”

Anticholinesterase Pesticides Interactions

“…The study concluded that the inhibition of malathion toxicity by chloramphenicol pre-treatment is attributable to inhibition of the metabolic activation of malathion to malaoxon by inhibition of the hepatic cytochrome P-450 monooxygenase system (Fig. 22.1) in rats and mice (Adams et al, 1977;Dixon and Fouts, 1962;Halpert and Neal, 1980). Interestingly, Sutiak and colleagues (1994) reported that chloramphenicol has a protective effect against parathion-induced pulmonary edema, which is probably related to inhibition of the lung cytochrome P-450 responsible for parathion conversion to paraoxon.…”