The role of different cytochrome P450 isoforms in in vitro chloroform metabolism

Testai, Emanuela; Curtis, Valentina De; Gemma, Simonetta; Fabrizi, Laura; Gervasi, P.G.; Vittozzi, Luciano

doi:10.1002/(sici)1522-7146(1996)11:6<305::aid-jbt6>3.0.co;2-o

Cited by 25 publications

(7 citation statements)

References 37 publications

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“…The present study demonstrates that interferences in THM elimination, observed following the administration of binary mixtures of THMs, affected all four chemicals and could be the consequence of reciprocal metabolic inhibition between them. This is reasonable, since these substances are metabolized by the same isoenzyme (CYP 2E1) (Testai et al, 1996;Nakajima et al, 1995;Lilly et al, 1997) and in accordance with the hypothesis of an interaction mechanism suggested by Da Silva et al (1999). Further, the PBTK model simulations for each THM obtained in this study are consistent with the occurrence of metabolic inhibition in binary mixtures of THMs.…”

Section: Discussionsupporting

confidence: 77%

Evaluation of the Pharmacokinetic Interactions Between Orally Administered Trihalomethanes in the Rat

Silva

Charest‐Tardif²,

Krishnan³

et al. 2000

Journal of Toxicology and Environmental Health, Part A

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The blood kinetics of trihalomethanes has recently been reported to differ between an oral administration of any single trihalomethane (0.25 mmol/kg) [THMs: chloroform, bromoform, bromodichloromethane (BDCM), dibromochloromethane (DBCM)] and a combined administration of 0.25 mmol/kg of each of the 4 THMs. The significant increase in blood concentrations of THMs could be a consequence of pharmacokinetic interactions between two or more of the THMs present simultaneously. The objective of the present study was to characterize the blood kinetics of THMs following oral administration singly or as binary mixtures in order to assess the relative contribution of each THM to the kinetic interferences observed with the quaternary mixture. A single dose of each THM (0.5 mmol/kg) alone or of a binary mixture containing 0.5 mmol/kg of each THM was administered by gavage to male Sprague-Dawley rats. The venous blood concentrations of unchanged THMs were measured for up to 720 min postadministration by headspace gas chromatography. Results showed that, compared to single administration, each binary mixture caused a significant increase in the blood concentrations of both THMs present and this effect increased with time. The impact, however, was not similar for each mixture, especially during the first hour following administration of the compounds (bromoform and DBCM). Among the four THMs, bromoform and DBCM kinetics appeared to be more sensitive to the mixture effect and to exert the greatest impact on the kinetics of the second THM present in the mixture. Simulation exercises conducted with physiologically based toxicokinetic models suggest metabolic inhibition as the possible mechanism of the interaction between THMs. In conclusion, the results of this study show that, at the dose level investigated, every binary combination of THMs, when orally administered, resulted in a significant modulation of their pharmacokinetics and suggest that this is probably the consequence of a mutual metabolic inhibition between the THMs.

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Section: Discussionsupporting

confidence: 77%

Evaluation of the Pharmacokinetic Interactions Between Orally Administered Trihalomethanes in the Rat

Silva

Charest‐Tardif²,

Krishnan³

et al. 2000

Journal of Toxicology and Environmental Health, Part A

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“…Cytotoxicity, defined as an alteration in the cell integrity, with or without DNA damage, has been related to chloroform and trichloroacetic acid (TCAA). Phosgene and dichloromethyl are intermediate products of chloroform after in vivo metabolism through cytochrome P450 2E1 (CYP2E1) [15]. Phosgene is highly reactive and binds to proteins, phospholipids, and reduced glutathione cell content [16].…”

Section: Experimental Evidence and Mechanisms Of Actionmentioning

confidence: 99%

Overview of Disinfection By-products and Associated Health Effects

Villanueva

Cordier²,

Font-Ribera

et al. 2015

Curr Envir Health Rpt

235

124

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The presence of chemical compounds formed as disinfection by-products (DBPs) is widespread in developed countries, and virtually whole populations are exposed to these chemicals through ingestion, inhalation, or dermal absorption from drinking water and swimming pools. Epidemiological evidence has shown a consistent association between long-term exposure to trihalomethanes and the risk of bladder cancer, although the causal nature of the association is not conclusive. Evidence concerning other cancer sites is insufficient or mixed. Numerous studies have evaluated reproductive implications, including sperm quality, time to pregnancy, menstrual cycle, and pregnancy outcomes such as fetal loss, fetal growth, preterm delivery, and congenital malformation. The body of evidence suggests only minor effects from high exposure during pregnancy on fetal growth indices such as small for gestational age (SGA) at birth. Populations highly exposed to swimming pools such as pool workers and professional swimmers show a higher prevalence of respiratory symptoms and asthma, respectively, although the direction of the association, and thus causality, is not clear among professional swimmers. The risk of asthma, wheezing, eczema, and other respiratory outcomes among children attending swimming pools has been the object of extensive research. Early studies suggested a positive association, while subsequent larger studies found no correlations or showed a protective association. Future research should develop methods to evaluate the effects of the DBP mixture and the interaction with personal characteristics (e.g., genetics, lifestyle), clarify the association between swimming pools and respiratory health, evaluate the occurrence of DBPs in lowand middle-income countries, and evaluate outcomes suggested by animal studies that have not been considered in epidemiological investigations.

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“…Still, it is possible that subsequent metabolism of the CCl 4 metabolite, CHCl 3 , could potentially skew results by decreasing the apparent rate of CCl 4 metabolism. Testai et al (1996) showed that anaerobic metabolism of CHCl 3 was not observable at 100 µM CHCl 3 , although some metabolism could be observed under anaerobic conditions at 5000 µM CHCl 3 . …”

Section: Lack Of Anaerobic Chcl 3 Metabolismmentioning

confidence: 99%

Improved Risk Estimates for Carbon Tetrachloride

Benson¹,

Springer²

1999

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The role of different cytochrome P450 isoforms in in vitro chloroform metabolism

Cited by 25 publications

References 37 publications

Evaluation of the Pharmacokinetic Interactions Between Orally Administered Trihalomethanes in the Rat

Evaluation of the Pharmacokinetic Interactions Between Orally Administered Trihalomethanes in the Rat

Overview of Disinfection By-products and Associated Health Effects

Improved Risk Estimates for Carbon Tetrachloride

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