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Oxidative transformation of hexachlorocyclohexane in rats and with rat liver microsomes

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Summary

  1. 1.

    A major metabolite of hexachlorocyclohexane (HCH) in rats, 2,4,6-trichlorophenol (2,4,6-TCP), is shown to accumulate in suspensions of rat liver microsomes incubated with HCH in the presence of NADPH and air. Evidence is presented for the involvement of cytochrome P-450. The rate of formation of 2,4,6-TCP differed for different configurations of HCH in an order corresponding roughly to that seen in vivo when daily urinary output of 2,4,6-TCP was estimated after i.p. application of HCH.

  2. 2.

    A reaction sequence is proposed for the formation of 2,4,6-TCP from HCH assuming hydroxylation to be the initial step. The sequence would explain the exclusive formation of symmetrical TCP obtained in vitro with the HCH-configurations alpha, beta, delta and epsilon. Chemical evidence supporting the hypothesis is included as is the result of experiments, both in vivo and in vitro, with isomers of pentachlorocyclohexene and of trichlorobenzene which excluded dehydrochlorination of HCH as the initial reaction. In addition, the differences which exist between isomers of HCH in the accessibility of carbon-hydrogen bonds are shown to provide a reasonably consistent explanation of the differences in rate recorded in vitro for their conversion to 2,4,6-TCP.

  3. 3.

    Gamma-HCH, in contrast to its isomers, was found to be converted by NADPH-substituted rat liver microsomes to several chlorophenols. Second in quantity to 2,4,6-TCP was a tetrachlorophenol, presumably the 2,3,4,6-isomer, which is known to be a prominent metabolite of gamma-HCH in rats. Evidence has been obtained which indicates that the formation of 2,4,6-TCP from gamma-HCH in vitro is largely independent of that of 2,3,4,6-tetrachlorophenol. It is suggested that the formation of the tetrachlorophenol may be the result of hydroxylation of the hexachlorocyclohexene which has recently been shown by others to be formed from gamma-HCH in a reaction involving cytochrome P-450.

  4. 4.

    With reference to similarly specific recognition by constituents of nervous tissue, the distinctive transformation, by hepatic enzymes, of HCH of the gamma-configuration is considered as to its cause by invoking the well known fact that gamma-HCH, unlike its isomers, undergoes ring inversion at ordinary temperatures.

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Abbreviations

HCH:

1,2,3,4,5,6-Hexachlorocyclohexane

PCH:

1,3,4,5,6-Pentachlorocyclohex-1-ene

TCB:

Trichlorobenzene

TCP:

Trichlorophenol

GC:

Gas liquid chromatography

MS:

Mass spectrometry

FID:

Flame ionisation detection

ECD:

Electron capture detection

TLC:

Thin layer chromatography

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  1. Institut für Toxikologie und Pharmakologie der Philipps-Universität Marburg, Pilgrimstein 2, D-3550, Marburg/Lahn, Germany

    K. Stein, J. Portig & W. Koransky

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  1. K. Stein
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  2. J. Portig
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  3. W. Koransky
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Stein, K., Portig, J. & Koransky, W. Oxidative transformation of hexachlorocyclohexane in rats and with rat liver microsomes. Naunyn-Schmiedeberg's Arch. Pharmacol. 298, 115–128 (1977). https://doi.org/10.1007/BF00508618

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  • DOI: https://doi.org/10.1007/BF00508618

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