Assessment of inhibition of porcine hepatic cytochrome P450 enzymes by 48 commercial drugs

Hu, Steve; Mazur, C.; Feenstra, Kenneth L.; Lorenz, Julie K.; Merritt, Dawn A.

doi:10.1016/j.tvjl.2016.03.011

Cited by 9 publications

(5 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…where J and J 0 represent OCT2-dependent transport activity determined in the presence and absence of the inhibitor, respectively, and I is the fixed inhibitor concentration (in this case, 20 mM). This approach gives reasonable inhibitor affinity estimates when the screening concentration is within the linear part of the IC 50 curve (i.e., approximately 10%-90% inhibition) (Gao et al, 2002;Kido et al, 2011;Hu et al, 2016); in the present study, this corresponded to IC 50 values between 2 and 180 mM.…”

Section: Methodssupporting

confidence: 58%

Assessment of Substrate-Dependent Ligand Interactions at the Organic Cation Transporter OCT2 Using Six Model Substrates

Sandoval

Zorn

Clark

et al. 2018

Molecular Pharmacology

View full text Add to dashboard Cite

Organic cation transporter (OCT) 2 mediates the entry step for organic cation secretion by renal proximal tubule cells and is a site of unwanted drug-drug interactions (DDIs). But reliance on decision tree-based predictions of DDIs at OCT2 that depend on IC values can be suspect because they can be influenced by choice of transported substrate; for example, IC values for the inhibition of metformin versus MPP transport can vary by 5- to 10-fold. However, it is not clear whether the substrate dependence of a ligand interaction is common among OCT2 substrates. To address this question, we screened the inhibitory effectiveness of 20 M concentrations of several hundred compounds against OCT2-mediated uptake of six structurally distinct substrates: MPP, metformin,,,-trimethyl-2-[methyl(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino]ethanaminium (NBD-MTMA), TEA, cimetidine, and 4-4-dimethylaminostyryl--methylpyridinium (ASP). Of these, MPP transport was least sensitive to inhibition. IC values for 20 structurally diverse compounds confirmed this profile, with IC values for MPP averaging 6-fold larger than those for the other substrates. Bayesian machine-learning models of ligand-induced inhibition displayed generally good statistics after cross-validation and external testing. Applying our ASP model to a previously published large-scale screening study for inhibition of OCT2-mediated ASP transport resulted in comparable statistics, with approximately 75% of "active" inhibitors predicted correctly. The differential sensitivity of MPP transport to inhibition suggests that multiple ligands can interact simultaneously with OCT2 and supports the recommendation that MPP not be used as a test substrate for OCT2 screening. Instead, metformin appears to be a comparatively representative OCT2 substrate for both in vitro and in vivo (clinical) use.

show abstract

Section: Methodssupporting

confidence: 58%

Assessment of Substrate-Dependent Ligand Interactions at the Organic Cation Transporter OCT2 Using Six Model Substrates

Sandoval

Zorn

Clark

et al. 2018

Molecular Pharmacology

View full text Add to dashboard Cite

show abstract

“…A more recent study has shown that TIA was an effective inhibitor of CYP450 activities in goat and cattle microsomes [ 35 ]. This is consistent with what has been found in previous studies that TIA acted as inhibitor of porcine hepatic CYP3A and CYP2C, respectively [ 26 ]. Moreover, the CYP450 content in broiler chickens was lower in contrast with horses, pigs, cattle, rabbits, and rats [ 55 , 56 ].…”

Section: Discussionsupporting

confidence: 93%

“…Because of the wide usage, a variety of antibiotics were found in livestock products, potentially posing health risks to the public due to antibiotics residues [ 25 ]. A study implied that lincomycin inhibits CYP1A, CYP2A, CYP2C, CYP2B, CYP2E and CYP3A in porcine liver microsomes at a concentration of 3 μM [ 26 ]. Amoxicillin inhibited CYP2C8 with an IC 50 of 830 µM by recombinant Escherichia coli [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Exploration of Cytochrome P450-Related Interactions between Aflatoxin B1 and Tiamulin in Broiler Chickens

Sun,

Lootens,

Kabeta

et al. 2024

Toxins

View full text Add to dashboard Cite

Poultry may face simultaneous exposure to aflatoxin B1 (AFB1) and tiamulin (TIA), given mycotoxin contamination and antibiotic use. As both mycotoxins and antibiotics can affect cytochrome P450 enzymes (CYP450), our study aimed to explore their interaction. We developed UHPLC-MS/MS methods for the first-time determination of the interaction between TIA and AFB1 in vitro and in vivo in broiler chickens. The inhibition assay showed the half maximal inhibitory concentration (IC50) values of AFB1 and TIA in chicken liver microsomes are more than 7.6 μM, indicating an extremely weak inhibitory effect on hepatic enzymes. Nevertheless, the oral TIA pharmacokinetic results indicated that AFB1 significantly increased the area under the plasma concentration-time curve (AUClast) of TIA by 167% (p < 0.01). Additionally, the oral AFB1 pharmacokinetics revealed that TIA increased the AUClast and mean residence time (MRT) of AFB1 by 194% (p < 0.01) and 136%, respectively. These results suggested that the observed inhibition may be influenced by other factors, such as transport. Therefore, it is meaningful to further explore transport and other enzymes, involved in the interaction between AFB1 and TIA. Furthermore, additional clinical studies are necessary to thoroughly assess the safety of co-exposure with mycotoxins and antibiotics.

show abstract

“…In food-producing species, inter-individual variability in xenobiotics metabolism might result in the accumulation of harmful residues in foodstuffs. Therefore, pharmacogenetic approaches are fundamental to either understand the fate of xenobiotics in the living animal than estimate the consumers' risk of exposure to noxious chemicals (Hu et al 2016;Jiang et al 2018;Giantin et al 2019). To improve our knowledge on this aspect, this study aims to measure the frequency of five harmful missense CYP3A SNVs in a population of Limousine cattle, a French meat cattle breed widely bred in Northern Italy (Mastrangelo et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Missense single nucleotide variants affecting CYP3A catalytic activity are present in Limousine cattle

Pauletto

Tolosi

Dacasto

et al. 2020

Italian Journal of Animal Science

View full text Add to dashboard Cite

Cytochrome P450 (CYP) 3A is one of the most important subfamily of drug metabolising enzymes. Genetic factors such as breed and allelic variants might modify CYP3A expression and enzyme activity and lead to inter-and intra-individual variability in clinical response or toxicity. Cattle CYP3A gene cluster has been recently re-sequenced in 300 Piedmontese cattle by deep targeted sequencing. Thirteen missense single nucleotide variants (SNVs) were identified, and for five of them an impact on CYP3A activity was demonstrated in vitro. In the present work, we assessed the genetic frequency of these five SNVs in Limousine, a cattle breed widely raised for meat production in Veneto Region. A total of 215 cows were genotyped using specific melting curve assays. Only two missense SNVs out of five, both located on CYP3A28 coding sequence, were detected: rs384467435 and rs454167819. The former mutant allele was present in homozygosis in the 4% of tested cows, while in heterozygosis in the 24% of animals. The second SNV was detected only in heterozygosis in 11 cows out of 215 (i.e. 4.9%). These findings suggest the presence of missense SNVs, proved to halve CYP3A28 catalytic activity, in both Limousine and Piedmontese meat cattle breeds. As a consequence, these SNVs might impact on the kinetics of xenobiotics metabolised by CYP3A, including drugs and natural toxins like ivermectin and aflatoxins, thereby resulting in toxicity or accumulation of harmful residues in foodstuffs. This result paves the way for new considerations on the fate of xenobiotics in cattle farming. HIGHLIGHTS Missense single nucleotide variants affecting CYP3A catalytic activity in vitro are present in Limousine and Piedmontese cattle breeds. Rs384467435 is the only missense single nucleotide variant for which the mutant allele is recorded in homozygosis in approximately 4% of Limousine and Piedmontese cattle. The polymorphisms here detected might affect the kinetics and the toxicity of xenobiotics metabolised by CYP3A in cattle.

show abstract

Assessment of inhibition of porcine hepatic cytochrome P450 enzymes by 48 commercial drugs

Cited by 9 publications

References 32 publications

Assessment of Substrate-Dependent Ligand Interactions at the Organic Cation Transporter OCT2 Using Six Model Substrates

Assessment of Substrate-Dependent Ligand Interactions at the Organic Cation Transporter OCT2 Using Six Model Substrates

Exploration of Cytochrome P450-Related Interactions between Aflatoxin B1 and Tiamulin in Broiler Chickens

Missense single nucleotide variants affecting CYP3A catalytic activity are present in Limousine cattle

Contact Info

Product

Resources

About