Structure–Activity Approach to the Identification of Environmental Estrogens: The MCASE Approach

Cunningham, Albert R.; Cunningham, Suzanne L.; Rosenkranz, Herbert S.

doi:10.1080/1062936032000169679

Cited by 12 publications

(8 citation statements)

References 40 publications

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“…For example, PhIP has been shown to possess structural attributes associated with mutagenicity and interaction with the estrogen receptor (55). Fragment set B is similar to biophores that we previously identified with MultiCASE as being related to estrogenic activity as measured in the E-SCREEN assay (56), and in a number of scenarios, estrogens have been demonstrated to be metabolized to genotoxic agents (57,58).…”

Section: Resultsmentioning

confidence: 74%

Structure−Activity Relationship Analysis of Rat Mammary Carcinogens

Cunningham

Moss

Iype

et al. 2008

Chem. Res. Toxicol.

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Structure-activity relationship (SAR) models are powerful tools to investigate the mechanisms of action of chemical carcinogens and to predict the potential carcinogenicity of untested compounds. We describe here the application of the cat-SAR (categorical-SAR) program to two learning sets of rat mammary carcinogens. One set of developed models was based on a comparison of rat mammary carcinogens to rat noncarcinogens (MC-NC), and the second set compared rat mammary carcinogens to rat nonmammary carcinogens (MC-NMC). On the basis of a leave-one-out validation, the best rat MC-NC model achieved a concordance between experimental and predicted values of 84%, a sensitivity of 79%, and a specificity of 89%. Likewise, the best rat MC-MNC model achieved a concordance of 78%, a sensitivity of 82%, and a specificity of 74%. The MC-NMC model was based on a learning set that contained carcinogens in both the active (i.e., mammary carcinogens) and the inactive (i.e., carcinogens to sites other than the mammary gland) categories and was able to distinguish between these different types of carcinogens (i.e., tissue specific), not simply between carcinogens and noncarcinogens. On the basis of a structural comparison between this model and one for Salmonella mutagens, there was, as expected, a significant relationship between the two phenomena since a high proportion of breast carcinogens are Salmonella mutagens. However, when analyzing the specific structural features derived from the MC-NC learning set, a dichotomy was observed between fragments associated with mammary carcinogenesis and mutagenicity and others that were associated with estrogenic activity. Overall, these findings suggest that the MC-NC and MC-NMC models are able to identify structural attributes that may in part address the question of "why do some carcinogens cause breast cancer", which is a different question than "why do some chemicals cause cancer".

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Section: Resultsmentioning

confidence: 74%

Structure−Activity Relationship Analysis of Rat Mammary Carcinogens

Cunningham

Moss

Iype

et al. 2008

Chem. Res. Toxicol.

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“…Some success has been achieved in in silico prediction of (chemical) sites of oxidation [ 205 – 207 ]. Because of the large database that has accumulated and the relative simplicity of mutagenesis, SAR has been useful in predicting genetic toxicology [ 208 , 209 ] but not as well for toxicity [ 201 , 210 ]. However, toxicology in vivo or even a single tissue is complex and can involve many events [ 193 ], many of which probably remain to be described, posing an ongoing challenge to safety assessment in the pharmaceutical industry.…”

Section: On-going Issuesmentioning

confidence: 99%

A history of the roles of cytochrome P450 enzymes in the toxicity of drugs

Guengerich

2020

Toxicol Res.

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The history of drug metabolism began in the 19th Century and developed slowly. In the mid-20th Century the relationship between drug metabolism and toxicity became appreciated, and the roles of cytochrome P450 (P450) enzymes began to be defined in the 1960s. Today we understand much about the metabolism of drugs and many aspects of safety assessment in the context of a relatively small number of human P450s. P450s affect drug toxicity mainly by either reducing exposure to the parent molecule or, in some cases, by converting the drug into a toxic entity. Some of the factors involved are enzyme induction, enzyme inhibition (both reversible and irreversible), and pharmacogenetics. Issues related to drug toxicity include drug-drug interactions, drug-food interactions, and the roles of chemical moieties of drug candidates in drug discovery and development. The maturation of the field of P450 and drug toxicity has been facilitated by advances in analytical chemistry, computational capability, biochemistry and enzymology, and molecular and cell biology. Problems still arise with P450s and drug toxicity in drug discovery and development, and in the pharmaceutical industry the interaction of scientists in medicinal chemistry, drug metabolism, and safety assessment is critical for success.

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“…Various EDCs are known to cause reproductive and developmental abnormalities and certain hormone-related cancers, such as prostate and breast cancers [3][4][5]. The potential consequences of human exposure to such endocrine disrupters has been the focus of much discussion [6]. Multiple in vivo and in vitro assays have been developed to test estrogenicity [7,8].…”

Section: Introductionmentioning

confidence: 99%

Uterotrophic effects of cow milk in immature ovariectomized Sprague–Dawley rats

Zhou

Qin

et al. 2009

Environ Health Prev Med

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Objectives Milk contains considerable quantities of estrogens and progesterone and as such may be one of the risk factors for hormone-related cancers. To determine the hormonal effects of commercial and traditional types of milk, we performed uterotrophic tests. Methods Forty-five rats were ovariectomized and divided into three groups of 15 animals each. The animals were kept for 7 days on powdered chow and one of three different liquids: commercial milk (C), traditional milk (T), or water. At autopsy, wet and dry uterine weights were determined. The cell heights of the uterine epithelium and endometrium were determined. The uterine 5-bromo-2-deoxyuridine (BrdU) labeling index of the epithelium and endometrium gland epithelium was also assessed. Results The weights of wet and dry uterus were 142 ± 13 and 112 ± 10 mg in the C group, 114 ± 30 and 91 ± 24 mg in the T group, and 87 ± 6 and 69 ± 5 mg in the W group. Significant differences in wet and dry uterus weights were found between all pairs of groups. The ratio of the wet uterine weight to body weight was significantly higher in the C and T groups than in the W group. The heights of the uterine epithelium and endometrium were higher and BrdU labeling index was greater in the C group than in the T and W groups. Conclusions Commercially available milk and traditional milk have uterotrophic effects on young ovariectomized rats. Our findings indicate that these uterotrophic effects in the milk groups were partly due to the estrogen and progesterone in the milk.

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Structure–Activity Approach to the Identification of Environmental Estrogens: The MCASE Approach

Cited by 12 publications

References 40 publications

Structure−Activity Relationship Analysis of Rat Mammary Carcinogens

Structure−Activity Relationship Analysis of Rat Mammary Carcinogens

A history of the roles of cytochrome P450 enzymes in the toxicity of drugs

Uterotrophic effects of cow milk in immature ovariectomized Sprague–Dawley rats

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