The oxidative metabolism of aldrin and dihydroaldrin by houseflies, housefly microsomes and pig liver microsomes and the effect of inhibitors

Brooks, G. T.; Harrison, A.

doi:10.1016/0006-2952(69)90080-x

Cited by 31 publications

(7 citation statements)

References 17 publications

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“…In addition, it was observed that ethylmorphine, hexobarbital, and chlorpromazine were mutually inhibitory, each retarding the metabolism of the other. These results were interpreted 44 ANDERS as evidence for a common enzyme pathway that accepts many drugs as sub stratcs. This then suggested that one drug inhibited the metabolism of an other by serving as an alternative substrate.…”

Section: Inhibitjon Of Drug Metabolismmentioning

confidence: 93%

“…These findings could explain the Competitive inhibition has been frequently observed when the effect of one drug on the metabolism of another is studied. Brooks & Harrison (44) showed that the hydroxylation of dihydroaldrin was competitively inhibited by dieldrin and a-hexachlorohexane and that the epoxidation of aldrin was similarly inhibited by dihydroaldrin and a-hexachlorohexane. The O-demeth ylatiol1 of p-nitroanisole was competitively inhibited by disulfiram and di ethyldithiocarbamate (45).…”

Section: Inhibitjon Of Drug Metabolismmentioning

confidence: 99%

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Enhancement and Inhibition of Drug Metabolism

Anders¹

1971

Annu. Rev. Pharmacol.

141

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A large number of factors can alter rates of drug metabolism. This re view wiII discuss the enhancement and inhibition of drug metabolism. By enhancement is meant that increase in rate of in vitro drug metabolism ob served following the inclusion of other drugs or chemicals in the reaction mixture. This term should be distinguished from the enzyme induction re sulting from treatment of the intact animal with other drugs or hydrocar bons. Inhibition of drug metabolism, as used in this review, refers to the blockage of metabolism of one drug by another at the enzymic site. This restriction excludes those agents that reduce rates of drug metabolism by mechanisms other than competition at enzymic sites, such as treatment with carbon tetrachloride (1), morphine (2), thyroxine (3) , and others. In addi tion, the review wiII be restricted to hepatic microsomal mixed function oxi dases; enhancement and inhibition of hydrolytic, reductive, and conjugative pathways will not be considered. ENHANCEMENT OF DRUG METABOLISMEthyl isocyanide.-Imai & Sato (4, 5) reported that EtNC exerts both stimulatory and inhibitory effects on microsomal aniline hydroxylation. The inhibitory effect of EtNC was attributed to a direct competition between oxygen and EtNC. The mechanism of the stimulatory effect appeared to be more complicated. The EtNC concentration producing maximal enhance ment was a function of the aniline concentration; as the aniline concentra tion was increased, more EtNC was needed to produce maximal enhance ment suggesting that hoth compounds were com peting for the same enzyme system. In addition, s pecies differences were observed in the activation of aniline hydroxylation by EtNC. The largest degree of enhancement was ob ta ined in the rabbit; in contrast, EtNC produced only inhibition of aniline

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Section: Inhibitjon Of Drug Metabolismmentioning

confidence: 93%

Section: Inhibitjon Of Drug Metabolismmentioning

confidence: 99%

Enhancement and Inhibition of Drug Metabolism

Anders¹

1971

Annu. Rev. Pharmacol.

141

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“…In addition, 4,5-dihydroaldrin (XII) has no metabolites which are analogous to either II or III (Brooks and Harrison, 1969). These results imply that the epoxide group is a prerequisite for formation of C-12 hydroxy compounds such as II, and that keto compounds such as III cannot be formed by direct attack on the dichlorovinyl group of I, but can only be formed when this dichlorovinyl group is id close proximity to a suitably activated position to receive its electrons, as would be the case if hydrogen abstraction at C-12 occurred to produce a common hybrid ion.…”

Section: Resultsmentioning

confidence: 99%

Major fecal metabolite of dieldrin in rat. Structure and chemistry

McKinney¹,

Matthews²,

Fishbein³

1972

J. Agric. Food Chem.

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The structure (C-12 jy «-hydroxy dieldrin) of the major fecal metabolite of dieldrin in the rat has been confirmed via pmr spectroscopy employing spin decoupling techniques and the new shift reagent, Eu(DPM)3. Detailed studies of the spectral and reaction properties of this metabolite have established the stereochemical structure and have shown that the system is susceptible to degradation. Evidence is presented which indicates that the major fecal metabolite in the rat cannot be converted to the major urinary metabolite but that a common intermediate hybrid ion (or radical) may exist in their formation from dieldrin. It is proposed that an activated dieldrin molecule may mimic certain male steroidal hormones or their precursors in regard to the capability of anchimeric participation of a double bond. Studiesof the metabolism and other degradative proc-I esses of dieldrin (I) continue to be complicated by difficulties in the unequivocal identification of the transformation products which generally require stereochemical structure proof. This difficulty in making positive structure assignments seems to be primarily due to the lack of substantial spectral and chemical data on related strained model systems. The only metabolite of dieldrin whose structure is unequivocal, having been confirmed by synthesis, is that of Zra«s-4,5-dihydroxy-4,5-dihydroaldrin. [The numbering system used herein for these compounds complies with that suggested by Benson (1969).] Since this metabolite was reported (Korte and Arent, 1965) to possess optical activity, it would be one of the enantiomers of this structure. Recent investigations in our laboratory (McKinney et al., 1971) employing proton magnetic resonance (pmr) spectroscopy including decoupling experiments and sample treatment with the new pmr shift reagent, tris(dipivalomethanato)europium [Eu(DPM)3], enabled the rapid and accurate stereochemical structure determination of some postulated chlorinated polycyclodiene pesticide metabolites.The purpose of this work was to test first the applicability of this pmr method for positive structure assignment of the major fecal metabolite of dieldrin in the rat for which most recent investigators (Baldwin et al., 1970a) have assigned structure II. Secondly, structure confirmation of this metabolite would render its conversion reactions more predictable, and since it is the primary metabolite excreted by the rat, its toxicological meaning in relation to the problems of environmental contamination should be carefully assessed. As a working hypothesis in the chemical studies, it was thought that if the assignment of the position of hydroxylation of dieldrin to the ostensibly aliphatic C-12 methylene group was correct and, if this hydroxyl group had a syn relationship to the epoxide group, conjugation or any other similarly activating derivatization would enable a rather facile rearrangement to occur with the formation of a bridged ketone of identical structure (III) to that proposed (Damico et al., 1968b) for the major urinary metabolite of d...

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“…In contrast to the conversion of aldrin and isodrin into their stable 6,7-epoxides, dieldrin and endrin (Giannotti et al, 1957;Kunze and Laug, 1953), 6,7-dihydroaldrin (9, Figure 96.1) and 6,7-dihydroisodrin (10) lacking the olefinic double bond, are monohydroxylated in the 6-(7) position by microsomal oxidases (Brooks, 1966;Brooks and Harrison, 1969a) and in vivo in houseflies. The stereoselective monohydroxylation of dihydroisodrin provided an alternative to the epoxidation reaction for the measurement of MFO activity (Krieger, 2008).…”

Section: Inhibitorsmentioning

confidence: 99%

Interactions with the Gamma-Aminobutyric Acid A-Receptor

Brooks¹

2010

Hayes' Handbook of Pesticide Toxicology

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The oxidative metabolism of aldrin and dihydroaldrin by houseflies, housefly microsomes and pig liver microsomes and the effect of inhibitors

Cited by 31 publications

References 17 publications

Enhancement and Inhibition of Drug Metabolism

Enhancement and Inhibition of Drug Metabolism

Major fecal metabolite of dieldrin in rat. Structure and chemistry

Interactions with the Gamma-Aminobutyric Acid A-Receptor

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