In vitro bioactivation of the environmental pollutant 3-methylsulphonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene in the human adrenal gland

Jonsson, C.-J.; Lund, Bert‐Ove

doi:10.1016/0378-4274(94)90177-5

Cited by 23 publications

(10 citation statements)

References 17 publications

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“…MeSO2-DDE is a potent toxicant for the adrenal cortex in mouse (13) and also in the human adrenal glands as observed as in vitro bioactivation of this compound in human adrenal gland (14). The irreversible binding of MeSO2-DDE in the zona fasciculata of the adrenals led to the formation of necrotic cells and inhibition of glucocorticoid hormone synthesis (13,41).…”

Section: Discussionmentioning

confidence: 99%

“…Metabolites of persistent environmental contaminants, however, may also have hydrophobic properties and can thus be accumulated in body, such as methyl sulfone metabol of chlorinated biphenyls (MeSO2-C and of DDE (MeSO2-DDE) (6,7), they may have specific protein-bind properties, such as certain MeSO2-C (8-11), hydroxy-CBs (12), and MeS( DDE (13,14). These properties lead to retention of certain MeSO2-CBs in lu kidney, and uterine fluid (8-10) a MeSO2-DDE in adrenal tissue (13,14).…”

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confidence: 99%

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Methylsulfonyl Metabolites of PCBs and DDE in Human Milk in Sweden, 1972-1992

Norén¹,

Lunden²,

Pettersson³

et al. 1996

Environmental Health Perspectives

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Methylsulfonyl Metabolites of PCBs and DDE in Human Milk in Sweden, 1972-1992

Norén¹,

Lunden²,

Pettersson³

et al. 1996

Environmental Health Perspectives

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“…Animal experiments have shown MeSO 2 -DDE to be adrenotoxic to several species after bioactivation in adrenal cortex mitochondria (3)(4)(5)(6)(7). Furthermore, human adrenal mitochondria have also been demonstrated to bioactivate MeSO 2 -DDE in vitro (8). It has been suggested, but never demonstrated, that the bioactivation is mediated by mitochondrial cytochrome P450 (7).…”

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confidence: 99%

Novel Involvement of a Mitochondrial Steroid Hydroxylase (P450c11) in Xenobiotic Metabolism

Lund

1995

Journal of Biological Chemistry

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Adrenocortical mitochondrial cytochrome P450 isozymes of the Cyp11 family normally synthesize steroids with a very strict substrate specificity. However, for the first time, P450c11 was additionally shown to metabolize and bioactivate the adrenotoxic environmental pollutant 3-methylsulfonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene (MeSO 2 -DDE). This conclusion is based on a striking correlation between inductions of MeSO 2 -DDE and deoxycorticosterone metabolism by forskolin in the adrenocortical cell lines Y1 and Kin-8, inhibition of P450c11-dependent activities in Y1 cells by MeSO 2 -DDE, and metabolism of MeSO 2 -DDE by non-steroidogenic COS cells after transfection with a cDNA encoding P450c11. The interaction between xenobiotics and glucocorticoid synthesis should focus more attention to xenobiotic-induced hormonal disturbances.MeSO 2 -DDE (3-methylsulfonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene)1 is a metabolite of the still extensively used insecticide DDT and is therefore a global environmental pollutant. Because of its lipophilicity and persistence, MeSO 2 -DDE is bioaccumulated in the food chain, even leading to pollution of human breast milk (1, 2). Animal experiments have shown MeSO 2 -DDE to be adrenotoxic to several species after bioactivation in adrenal cortex mitochondria (3-7). Furthermore, human adrenal mitochondria have also been demonstrated to bioactivate MeSO 2 -DDE in vitro (8). It has been suggested, but never demonstrated, that the bioactivation is mediated by mitochondrial cytochrome P450 (7). The adrenal gland contains several P450 isozymes, but in contrast to hepatic P450s, adrenal P450s are generally not active in xenobiotic metabolism. The genes encoding the mitochondrial P450 11␤-hydroxylase (P450c11), cholesterol side-chain cleavage (P450scc), and aldosterone synthase (P450aldo) belong to the Cyp11 subfamily of the P450 superfamily of genes (9). These enzymes show a strict substrate specificity and are therefore not believed to metabolize xenobiotics. P450scc is the first and rate-limiting enzyme in steroid hormone synthesis, localized in all steroidogenic tissues, whereas P450c11 and P450aldo are specifically localized in the adrenal cortex. The latter two participate as the last enzymes in the synthesis of glucocorticoids and mineralocorticoids, respectively. Given the specific mitochondrial damage in the adrenal cortex after MeSO 2 -DDE exposure, we decided to investigate the possible involvement of steroidogenic mitochondrial P450s in the metabolism of MeSO 2 -DDE. For this purpose we studied the bioactivation of MeSO 2 -DDE, i.e. the metabolic formation of reactive MeSO 2 -DDE intermediates capable of binding irreversibly to macromolecules or cellular antioxidants, in the mouse adrenocortical tumor cell line Y1. We also studied the bioactivation of MeSO 2 -DDE in a mutant of the Y1 cell line, Kin-8, that harbors a defect in the cAMP-dependent protein kinase (10), which normally participates in the hormonal regulation of the steroid-metabolizing enzymes. In Kin-8 cells,...

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“…Methylsulfonyl metabolites of CBs and p,p'-DDE are persistent and, due to their lipophilic character, they accumulate in adipose tissue (6)(7)(8). They may also have specific protein-binding properties that cause them to be retained in the body, e.g., 3-MeSO2-DDE in adrenal tissue (9,10) and certain MeSO2-CBs in lung, kidney, and uterine fluid (11)(12)(13), as demonstrated in experimental animals.…”

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confidence: 99%

“…3-MeSO2-DDE is a potent toxicant for the adrenal cortex, e.g., in mice (9) and probably also in humans, as suggested by in vitro studies, showing that 3-MeSO2-DDE is bioactivated to a tissue-binding metabolite by the human adrenal gland (10). and extracted with hexane/2-propanol (20 ml, 3/2 v/v).…”

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confidence: 99%