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Chemical Compound Review

Metox     1-methoxy-4-[2,2,2-trichloro- 1-(4...

Synonyms: Maralate, Marlate, Methoxo, Higalmetox, Methoxcide, ...
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Disease relevance of methoxychlor

  • From the studies reviewed here, the reproductive toxicity of methoxychlor is evident, but the significance of this toxicity with respect to human health remains to be determined [1].
  • Methoxychlor ( MeOCL ), a chlorinated hydrocarbon pesticide, was administered by oral gavage for 70 days to male and 14 days to female rats at dose levels of 100 and 200 mg/kg/day of body weight [2].
  • The incidences of carcinomas of the liver were increased in C3H male mice and BALB/c male and female mice fed methoxychlor [3].
  • Organisms exposed to 10 micrograms/l methoxychlor for 30 days showed enlarged thyroid glands with follicular hyperplasia [4].
  • Methoxychlor treatment delayed puberty by as much as 10 weeks and reduced fertility and copulatory plug formation in a dose-related manner at the initial mating [5].

Psychiatry related information on methoxychlor


High impact information on methoxychlor

  • In this study, we characterize the ERalpha, ERbeta, and AR activity of structurally related methoxychlor metabolites [8].
  • Interaction of methoxychlor and related compounds with estrogen receptor alpha and beta, and androgen receptor: structure-activity studies [8].
  • The trihydroxy metabolite of methoxychlor displayed only weak ERalpha agonist activity and did not alter ERbeta or AR activities [8].
  • We present a series of studies on the effects of exposure during fetal life to low, environmentally relevant doses of two pesticides, o,p'DDT and methoxychlor, and of low doses of the synthetic estrogen, diethylstilbestrol on subsequent neuro-behavioral development in house mice [6].
  • (4) The rate of depositing urine marks in a novel environment was increased in males prenatally exposed to DES, and also to o,p'DDT and methoxychlor [6].

Chemical compound and disease context of methoxychlor


Biological context of methoxychlor


Anatomical context of methoxychlor

  • Methoxychlor is also carcinogenic for the testis of BALB/c male mice, bone of B6C3F1 female mice, and the ovary of Osborne-Mendel female rats [3].
  • Previous investigations demonstrated that the incubation of the chlorinated hydrocarbon pesticide methoxychlor [1,1,1-trichloro-2,2-bis(4-methoxyphenyl)ethane] with rat liver microsomes generates phenolic estrogenic metabolites [18].
  • While a variety of natural and synthetic estrogens and xenoestrogens were inactive in this system, the proestrogenic pesticide methoxychlor was a surprisingly potent inhibitor of progesterone-induced oocyte maturation (median inhibitive concentration, 72 nM) [19].
  • Neoplasms of the pituitary, adrenals, and mammary gland were also increased in methoxychlor-treated female rats [3].
  • Furthermore, the time course of methoxychlor metabolism by PB microsomes demonstrated a rapid appearance and disappearance of the monohydroxy metabolite with the subsequent formation of the dihydroxy and trihydroxy metabolites [18].

Associations of methoxychlor with other chemical compounds


Gene context of methoxychlor

  • Methoxychlor and S-mephenytoin inhibited expressed CYP2B6 but not CYP1A2 mediated 7-EFC O-deethylation [23].
  • In this investigation, we report that CYP3A4 requires a phenolic function for ortho hydroxylation of estradiol and mono-O-demethylated methoxychlor and that CYP3A4 aromatic hydroxylation in general may be dependent on the presence of a free phenolic group [14].
  • Based on the totality of the evidence, CYP2C19 appears to be the major catalyst of methoxychlor mono-O-demethylation [24].
  • Although CYP2C18 is an efficient methoxychlor demethylase, its expression in liver is reportedly low or absent, suggesting a negligible role for this enzyme in methoxychlor metabolism [24].
  • Since it was previously shown that human liver microsomes demethylate methoxychlor mainly into S-mono-OH-M, the observation that UGT1A isoforms preferentially glucuronidate the S-mono-OH-M suggests a suitable mechanism for eliminating this major enantiomer [25].

Analytical, diagnostic and therapeutic context of methoxychlor


  1. Methoxychlor as a model for environmental estrogens. Cummings, A.M. Crit. Rev. Toxicol. (1997) [Pubmed]
  2. Effect of methoxychlor on reproductive systems of the rat. Bal, H.S. Proc. Soc. Exp. Biol. Med. (1984) [Pubmed]
  3. Carcinogenicity and toxicity of methoxychlor. Reuber, M.D. Environ. Health Perspect. (1980) [Pubmed]
  4. Evaluation of the developmental and reproductive toxicity of methoxychlor using an anuran (Xenopus tropicalis) chronic exposure model. Fort, D.J., Thomas, J.H., Rogers, R.L., Noll, A., Spaulding, C.D., Guiney, P.D., Weeks, J.A. Toxicol. Sci. (2004) [Pubmed]
  5. The estrogenic and antiandrogenic pesticide methoxychlor alters the reproductive tract and behavior without affecting pituitary size or LH and prolactin secretion in male rats. Gray, L.E., Ostby, J., Cooper, R.L., Kelce, W.R. Toxicology and industrial health. (1999) [Pubmed]
  6. Prenatal exposure to endocrine disrupting chemicals: effects on behavioral development. Palanza, P., Morellini, F., Parmigiani, S., vom Saal, F.S. Neuroscience and biobehavioral reviews. (1999) [Pubmed]
  7. Combined effects of dietary phytoestrogen and synthetic endocrine-active compound on reproductive development in Sprague-Dawley rats: genistein and methoxychlor. You, L., Casanova, M., Bartolucci, E.J., Fryczynski, M.W., Dorman, D.C., Everitt, J.I., Gaido, K.W., Ross, S.M., Heck Hd, H. Toxicol. Sci. (2002) [Pubmed]
  8. Interaction of methoxychlor and related compounds with estrogen receptor alpha and beta, and androgen receptor: structure-activity studies. Gaido, K.W., Maness, S.C., McDonnell, D.P., Dehal, S.S., Kupfer, D., Safe, S. Mol. Pharmacol. (2000) [Pubmed]
  9. Methoxychlor metabolites may cause ovarian toxicity through estrogen-regulated pathways. Miller, K.P., Gupta, R.K., Flaws, J.A. Toxicol. Sci. (2006) [Pubmed]
  10. Inhibition of androgen receptor-dependent transcriptional activity by DDT isomers and methoxychlor in HepG2 human hepatoma cells. Maness, S.C., McDonnell, D.P., Gaido, K.W. Toxicol. Appl. Pharmacol. (1998) [Pubmed]
  11. Low-dose bioactivity of xenoestrogens in animals: fetal exposure to low doses of methoxychlor and other xenoestrogens increases adult prostate size in mice. Welshons, W.V., Nagel, S.C., Thayer, K.A., Judy, B.M., Vom Saal, F.S. Toxicology and industrial health. (1999) [Pubmed]
  12. The effect of raloxifene on the uterine weight response in immature mice exposed to 17beta-estradiol, 1,1,1-trichloro-2, 2-bis(p-chlorophenyl)ethane, and methoxychlor. Al-Jamal, J.H., Dubin, N.H. Am. J. Obstet. Gynecol. (2000) [Pubmed]
  13. Methoxychlor disrupts uterine Hoxa10 gene expression. Fei, X., Chung, H., Taylor, H.S. Endocrinology (2005) [Pubmed]
  14. Catalytic characteristics of CYP3A4: requirement for a phenolic function in ortho hydroxylation of estradiol and mono-O-demethylated methoxychlor. Stresser, D.M., Kupfer, D. Biochemistry (1997) [Pubmed]
  15. Activated estrogens and antiestrogens: a 30-year journey with David Kupfer. Craig Jordan, V. Drug Metab. Rev. (2006) [Pubmed]
  16. Disruption of rat estrous cyclicity by the environmental estrogen 4-tert-octylphenol. Blake, C.A., Ashiru, O.A. Proc. Soc. Exp. Biol. Med. (1997) [Pubmed]
  17. Studies on the formation of methoxychlor-protein adduct in rat and human liver microsomes. Is demethylation of methoxychlor essential for cytochrome P450 catalyzed covalent binding? Bulger, W.H., Kupfer, D. Biochem. Pharmacol. (1990) [Pubmed]
  18. Metabolism of methoxychlor by hepatic P-450 monooxygenases in rat and human. 1. Characterization of a novel catechol metabolite. Kupfer, D., Bulger, W.H., Theoharides, A.D. Chem. Res. Toxicol. (1990) [Pubmed]
  19. Effects of endocrine-disrupting contaminants on amphibian oogenesis: methoxychlor inhibits progesterone-induced maturation of Xenopus laevis oocytes in vitro. Pickford, D.B., Morris, I.D. Environ. Health Perspect. (1999) [Pubmed]
  20. Role of hepatic monooxygenases in generating estrogenic metabolites from methoxychlor and from its identified contaminants. Bulger, W.H., Feil, V.J., Kupfer, D. Mol. Pharmacol. (1985) [Pubmed]
  21. Biosynthetic incorporation of fluorescent carbazolylundecanoic acid into membrane phospholipids of LM cells and determination of quenching constants and partition coefficients of hydrophobic quenchers. Omann, G.M., Glaser, M. Biochemistry (1984) [Pubmed]
  22. Intramolecular deuterium isotope effect and enantiotopic differentiation in oxidative demethylation of chiral [monomethyl-d3]methoxychlor in rat liver microsomes. Ichinose, R., Kurihara, N. Biochem. Pharmacol. (1987) [Pubmed]
  23. Examination of purported probes of human CYP2B6. Ekins, S., VandenBranden, M., Ring, B.J., Wrighton, S.A. Pharmacogenetics (1997) [Pubmed]
  24. Human cytochrome P450-catalyzed conversion of the proestrogenic pesticide methoxychlor into an estrogen. Role of CYP2C19 and CYP1A2 in O-demethylation. Stresser, D.M., Kupfer, D. Drug Metab. Dispos. (1998) [Pubmed]
  25. Glucuronidation of the oxidative cytochrome P450-mediated phenolic metabolites of the endocrine disruptor pesticide: methoxychlor by human hepatic UDP-glucuronosyl transferases. Hazai, E., Gagne, P.V., Kupfer, D. Drug Metab. Dispos. (2004) [Pubmed]
  26. Enhanced biodegradation of methoxychlor in soil under sequential environmental conditions. Fogel, S., Lancione, R.L., Sewall, A.E. Appl. Environ. Microbiol. (1982) [Pubmed]
  27. Development of androgen- and estrogen-responsive bioassays, members of a panel of human cell line-based highly selective steroid-responsive bioassays. Sonneveld, E., Jansen, H.J., Riteco, J.A., Brouwer, A., van der Burg, B. Toxicol. Sci. (2005) [Pubmed]
  28. Cognitive testing (delayed non-match to sample) during oral treatment of female adolescent monkeys with the estrogenic pesticide methoxychlor. Golub, M.S. Neurotoxicology and teratology. (2002) [Pubmed]
  29. The pesticide methoxychlor disrupts the fusion of myoblasts into myotubes in skeletal muscle cell culture. Grow, W.A., Eroschenko, V.P. Toxicol. Appl. Pharmacol. (2002) [Pubmed]
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