Format

Send to

Choose Destination
See comment in PubMed Commons below
Toxicol In Vitro. 2014 Aug;28(5):732-41. doi: 10.1016/j.tiv.2014.03.004. Epub 2014 Mar 14.

Modulation of trichloroethylene in vitro metabolism by different drugs in human.

Author information

1
TOXEN, Département des sciences biologiques, Université du Québec à Montréal, C.P. 8888 Succ. Centre-ville, Montreal, Qc. H3C 3P8, Canada.
2
Département de Santé environnementale et santé au travail, IRSPUM, Faculté de Médecine, Université de Montréal, C.P. 6128 Succ. Centre-ville, Montreal, Qc. H3C 3J7, Canada. Electronic address: sami.haddad@umontreal.ca.

Abstract

Toxicological interactions with drugs have the potential to modulate the toxicity of trichloroethylene (TCE). Our objective is to identify metabolic interactions between TCE and 14 widely used drugs in human suspended hepatocytes and characterize the strongest using microsomal assays. Changes in concentrations of TCE and its metabolites were measured by headspace GC-MS. Results with hepatocytes show that amoxicillin, cimetidine, ibuprofen, mefenamic acid and ranitidine caused no significant interactions. Naproxen and salicylic acid showed to increase both TCE metabolites levels, whereas acetaminophen, carbamazepine and erythromycin rather decreased them. Finally, diclofenac, gliclazide, sulphasalazine and valproic acid had an impact on the levels of only one metabolite. Among the 14 tested drugs, 5 presented the most potent interactions and were selected for confirmation with microsomes, namely naproxen, salicylic acid, acetaminophen, carbamazepine and valproic acid. Characterization in human microsomes confirmed interaction with naproxen by competitively inhibiting trichloroethanol (TCOH) glucuronidation (Ki=2.329 mM). Inhibition of TCOH formation was also confirmed for carbamazepine (partial non-competitive with Ki=70 μM). Interactions with human microsomes were not observed with salicylic acid and acetaminophen, similar to prior results in rat material. For valproic acid, interactions with microsomes were observed in rat but not in human. Inhibition patterns were shown to be similar in human and rat hepatocytes, but some differences in mechanisms were noted in microsomal material between species. Next research efforts will focus on determining the adequacy between in vitro observations and the in vivo situation.

KEYWORDS:

Drugs; Human; Inhibition; Interactions; Rat; Trichloroethylene

PMID:
24632077
DOI:
10.1016/j.tiv.2014.03.004
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Support Center