Implication of human drug transporters to toxicokinetics and toxicity of pesticides

Abstract

Human membrane drug transporters are recognized as major actors of pharmacokinetics. Pesticides also interact with human drug transporters, which may have consequences for pesticide toxicokinetics and toxicity. The present review summarizes key findings about this topic. In vitro assays have demonstrated that some pesticides, belonging to various chemical classes, modulate drug transporter activity, regulate transporter expression and/or are substrates, thus bringing the proof of concept for pesticide‐transporter relationships. The expected low human concentration of pesticides in response to environmental exposure constitutes a key‐parameter to be kept in mind for judging the in vivo relevance of such pesticide‐transporter interactions and their consequences for human health. Existing data about interactions of pesticides with drug transporters remain, however, rather sparse; more extensive and systematic characterization of pesticide‐transporter relationships, through the use of high throughput in vitro assays and/or in silico methods, is, therefore, required. In addition, consideration of transporter polymorphisms, pesticide mixture effects and physiological and pathological factors governing drug transporter expression may help to better define the in vivo relevance of pesticide‐transporter interactions in terms of toxicokinetics and toxicity for humans. © 2019 Society of Chemical Industry

Differential interactions of carbamate pesticides with drug transporters

“…The present study demonstrates that some carbamate pesticides inhibit drug transporter activities, thus adding such chemicals to the growing list of agrochemicals interacting with drug transporters. As already demonstrated for other classes of pesticides like organochlorine, pyrethroid and organophosphorus pesticides (Gueniche et al, 2020), the inhibition of transporter activity by carbamates depends on the nature of the pesticide and of the transporter. The N-methylcarbamates aminocarb and carbofuran thus rather poorly interact with ABC and SLC drug transporters, whereas chlorpropham inhibits BCRP and OAT3…”

“…Luminal gut concentrations of chlorpropham and propamocarb, although in the 30-200 µM range for oral ingestion of the ADI dose, are also A c c e p t e d M a n u s c r i p t insufficient for inhibiting in vivo intestinal BCRP or OCT1. Other pesticides interacting with drug transporters in cultured cells, such as the pyrethoids allethrin and tetramethrin and some organophosphorus pesticides, have similarly been hypothesised to fail to alter transporter activities in environmentally-or occupationally-exposed humans (Chedik et al, 2019;Chedik et al, 2017a;Gueniche et al, 2020). It should however be kept in mind that humans are often exposed to mixtures of pesticides and/or other environmental pollutants like plasticizers, whose inhibitory effects towards drug transporters may add or synergize, as already demonstrated for inhibition of P-gp by pesticide combinations (Pivcevic and Zaja, 2006) or marine pollutants (Nicklisch et al, 2016).…”

“…It should however be kept in mind that humans are often exposed to mixtures of pesticides and/or other environmental pollutants like plasticizers, whose inhibitory effects towards drug transporters may add or synergize, as already demonstrated for inhibition of P-gp by pesticide combinations (Pivcevic and Zaja, 2006) or marine pollutants (Nicklisch et al, 2016). Exposure to such mixtures may consequently have to be considered for judging the in vivo relevance of transporter inhibition by pollutants, including carbamate pesticides (Gueniche et al, 2020). This assertion may be notably valuable for agricultural workers, often exposed to high concentrations of pesticides in an occupational manner (Mostafalou and Abdollahi, 2017).…”

“…This notably concerns agrochemicals, belonging to different main chemical classes of pesticides (Buss and Callaghan, 2008;Chedik et al, 2018). Thus, some organochlorine, pyrethroid or organophosphorus pesticides, used at concentrations in the 1-100 µM range, in vitro inhibited activities of various ABC and/or SLC transporters (Bain and LeBlanc, 1996;Bucher et al, 2014;Chedik et al, 2019;Chedik et al, 2017a;Gueniche et al, 2020), whereas, by contrast, neonicotinoid pesticides rather poorly blocked drug transporter activities (Le Vee et al, 2019). Inhibition of transporter activities depends on the nature of the pesticide and of the transporter.…”

“…If the concept that pesticides can interact with drug transporters is now well-established, as illustrated above, only a relatively small fraction of the total number of pesticides presently used in the world (more than 1000) has however been so far studied for potential interactions with drug transporters (Gueniche et al, 2020). Experimental data with respect to this topic remain thus limited.…”