Constitutive expression and phenobarbital modulation of drug metabolizing enzymes and related nuclear receptors in cattle liver and extra-hepatic tissues

Abstract

In humans and rodents, phenobarbital (PB) induces hepatic and extra-hepatic drug metabolizing enzymes (DMEs) through the activation of specific nuclear receptors (NRs).In contrast, few data about PB transcriptional effects in veterinary species are available.2. The constitutive expression and modulation of PB-responsive NR and DME genes, following an oral PB challenge, were investigated in cattle liver and extra-hepatic tissues (duodenum, kidney, lung, testis, adrenal and muscle).3. Likewise to humans and rodents, target genes were expressed to a lower extent compared to the liver with few exceptions. 4. Phenobarbital significantly affected hepatic CYP2B22, 2C31, 2C87, 3A and UDPglucuronosyltransferase 1A1-like, glutathione S-transferase A1-like and sulfotransferase 1A1-like (SULT1A1-like) mRNAs and apoprotein amounts; in extra-hepatic tissues, only duodenum showed a significant down-regulation of SULT1A1-like gene and apoprotein. Nuclear receptor mRNAs were never affected by PB. 5. Presented data are the first evidence about the constitutive expression of foremost DME and NR genes in cattle extra-hepatic tissues, and data obtained following a PB challenge are suggestive of species-differences in drug metabolism; altogether, these information are of value for the extrapolation of pharmacotoxicological data among species, the characterization of drug-drug interactions as well as the animal and consumer's risk caused by harmful residues formation.

Independent Predictors of Delay in Emergence From General Anesthesia

“…28 Clonazepam has also been shown to have no induction effect on CYP1A2 and CYP3A4 in vitro, 29,30 and is reportedly clinically safe in drug interactions. 30 Although phenobarbital induces CYP2B2, CYP2B6, CYP2C, CYP3A, and UGT1A-like mRNAs, [11][12][13] a direct effect on propofol metabolism has never been examined. Thus, although these 3 drugs are suggested to have an induction effect on CYPs, any effect of changes in the mechanism of drug metabolism induced by AEDs seems to be less than a direct pharmacological effect on the clinical enhancing effect of propofol.…”

Absolute quantification and modulation of cytochrome P450 3A isoforms in cattle liver

“…Phenobarbital is a well-known inducer of DMEs (CYP2A, 2B, 2C and 3A, various transferases) and drug transporters (Zancanella et al, 2012(Zancanella et al, , 2013. In cattle, a PB inducing dosage regimen has been recently shown to up-regulate CYP2B, 2C and 3A gene expressions (Zancanella et al, 2012).…”

“…In cattle, a PB inducing dosage regimen has been recently shown to up-regulate CYP2B, 2C and 3A gene expressions (Zancanella et al, 2012). In humans, despite the large overlap in sub- Valdostana (VALD, n = 5) liver aliquots, and mRNA levels were measured by quantitative real-time RT-PCR.…”

“…Among xenobiotics, the non-specific and pleiotropic CYP inducer phenobarbital (PB) has been shown to increase hepatic CYP3A mRNA levels and apoprotein amounts in cattle (Zancanella et al, 2012), and similarly in humans, rodent model species, dogs and pigs (Madan et al, 2003;Anakk et al, 2004;Graham et al, 2006;Magnusson et al, 2006;Puccinelli et al, 2010). In contrast, unexpected results have been observed following the exposure to a known human CYP3A inducer like dexamethasone (Greger and Blum, 2007;Cantiello et al, 2009).…”

“…Three animals served as controls (CTRL), while the other individuals (PB group) were given PB orally for 7 days at a dose rate of 18 mg/kg/day (Zancanella et al, 2012).…”