Effects of several organophosphates on hepatic cytochrome P450 activities in rats

Abstract

Four commonly used organophosphates (fenitrothion, dichlorvos, chlorpyrifos, and trichlorfon) were orally administered to male Sprague-Dawley rats for five days in order to explore their effects on the activities of liver cytochrome P450 (CYP). In addition, Michaelis-Menten kinetics of the metabolic reactions catalyzed by liver CYPs were analyzed following the addition of these compounds to the assay system to examine their potential inhibitory effects on liver CYPs activities. These reactions included ethoxyresorufin O-deethylation, midazolam 4-hydroxylation, tolbutamide hydroxylation, and bufuralol 1'-hydroxylation for CYP1A, 3A, 2C, and 2D activities, respectively. Total CYP content was also examined after oral administration of each organophosphate. Results revealed that oral giving of fenitrothion inhibited significantly CYP1A and 3A activities while elevated activity of CYP2C. Fenitrothion is a potent inhibitor for CYP1A and 2C with Ki values of 0.42 and 36.1 μM, respectively but had a weak inhibitory effect on CYP2D and 3A with Ki values of 290 and 226 μM, respectively. Chlorpyrifos is a potent inhibitor of CYP1A with Ki 0.24 μM and moderately inhibited CYP2C or 3A with Ki values of 84.8 and 77.7 μM, respectively. On the other hand, dichlorvos and trichlorfon caused extremely low or negligible inhibition of different CYP activities. From these results, it is concluded that both fenitrothion and chlorpyrifos may increase the toxicity of chemicals in environmental living organisms through their potent inhibitory effects on these CYP activities, but dichlorvos and trichlorfon may not.

Effects of acaricides on the activities of monooxygenases in bovine liver microsomes

“…On the other hand, as DCV is an oxon compound and is not subjected to oxidative desulfuration in the liver, this compound exhibited low inhibition potency against all oxidative activities tested (see Figures 1a-e and Table 2). This fact is in agreement with previous observations on the low or negligible inhibitory effects of this OP compound against CYP-dependent metabolic reactions in rats (Abdou et al, 2020).…”

“…It has been suggested that CYP inhibition by OPs containing a phosphorothionate group is a consequence of the release of reactive sulphur during this oxidative desulfuration (Butler & Murray, 1997; Hodgson & Rose, 2007). Thus, inhibition of different CYPs, including those involved in their metabolism, has been widely described, at least in rats (Abdou et al, 2020) and humans (Abass et al, 2009; Abass & Pelkonen, 2013; Hodgson & Rose, 2006).…”

“…For instance, a 98% inhibition of the CYP3A4‐dependent testosterone 6β‐hydroxylase activity was observed in presence 2 μ m of this OP (Usmani et al, 2003). Furthermore, in rat liver microsomes, CPF resulted a potent inhibitor of CYP1A1‐dependent metabolism, but a moderate inhibitor of CYP2C‐ and CYP3A‐mediated enzyme reactions (Abdou et al, 2020). In our work, only MROD (CYP1A2‐dependent) and BZ N‐oxidase (FMO‐mediated) enzyme activities were inhibited in presence of CPF (see Figure 1b and Table 2), but at the highest concentration of the acaricide tested (100 μ m ).…”

Developmental deficits in male rat pups caused by maternal and dietary administration of chlorpyriphos and cypermethrin: Melatonin’s mitigating effect

“…Pesticides are used widely to promote crop yield and eradicate pests (Abdou et al, 2020). Unfortunately, their environmental levels are a global issue of concern (Taiwo, 2019).…”

Gentamicin and tigecycline combined treatment‐potentiated liver injury in rats

“…The liver is the most responsible organ for the detoxification and removal of toxic chemicals, xenobiotics, and different medications (Abdou et al 2020; Soliman et al 2022a,b). Because of this, even at therapeutic levels, any drug might have an adverse effect on the liver (Osterreicher and Trauner, 2012).…”