Impact of age on hepatic cytochrome P450 of domestic male Camborough‐29 pigs

Hu, Steve

doi:10.1111/jvp.12163

Cited by 12 publications

(19 citation statements)

References 67 publications

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“…The midazolam 1′‐hydroxylation was very low at day 1, was significantly raised at two weeks of age and remained at a similar lever until five weeks of age. From five weeks onwards, a linear increase was present till 20 weeks of age . These activity data are also in agreement with the age‐related trend in human beings.…”

Section: Discussionsupporting

confidence: 89%

“…Also in our study, ketoconazole clearly inhibited the metabolism of Luciferin‐IPA in both HLM and minipig liver microsomes. Testosterone and midazolam are two commonly used CYP3A4 substrates in human beings, and also in pigs, they are metabolized by CYP3A . Co‐incubation of Luciferin‐IPA with testosterone or midazolam resulted in a reduction of the biotransformation of Luciferin‐IPA in the minipig liver microsomes.…”

Section: Discussionmentioning

confidence: 99%

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Age-related Differences in CYP3A Abundance and Activity in the Liver of the Göttingen Minipig

Peer

Bock

Boussery

et al. 2015

Basic Clin Pharmacol Toxicol

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In view of paediatric drug development, regulatory authorities often request safety studies in juvenile animals, including minipigs. Unfortunately, knowledge on the ontogeny of the biotransformation processes in animal models remains scarce and impedes a correct interpretation of the toxicity findings. CYP3A4 is one of the most important drug-metabolizing enzymes in human beings and shows important similarities with CYP3A in the minipig. Therefore, the aim of this study was to assess the abundance and activity of CYP3A in liver microsomes from foetal, juvenile (days 1, 3, 7 and 28) and adult male and female G€ ottingen minipigs. CYP3A abundance was studied by an indirect enzyme-linked immunosorbent assay (ELISA), whereas CYP3A activity was assessed by a biotransformation assay with Luciferin-IPA. CYP3A abundance could not be detected until day 3. From day 7 onwards, a gradual increase in expression was noted, leading to the highest abundance in adult animals. CYP3A activity was not detectable in foetuses and 1-day-old animals. The CYP3A activity was detectable, but below the LLOQ in day 3 animals and increased gradually with age to reach the highest level in adults. The CYP3cide and ketoconazole inhibition, and testosterone and midazolam reduction of Luciferin-IPA metabolism in minipig liver microsomes substantiate that Luciferin-IPA is metabolized by CYP3A in minipigs. A positive correlation was found between CYP3A abundance and biotransformation of Luciferin-IPA (Pearson r = 0.863; p < 0.0001). In conclusion, both abundance and activity of CYP3A increased gradually in juvenile minipigs, but remained below the levels observed in adult animals.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Age-related Differences in CYP3A Abundance and Activity in the Liver of the Göttingen Minipig

Peer

Bock

Boussery

et al. 2015

Basic Clin Pharmacol Toxicol

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“…Similar age patterns have been observed in cattle (Shoaf et al ., ; Greger et al ., ) and rats (Pacifici & Rane, ; Chengelis, ). This pattern is more obvious when the capacity of conjugation is expressed with multiplying intrinsic clearance with ratio of liver‐to‐body weights because the ratio of liver‐to‐body weights is obviously lower at older ages (Hu, ).…”

Section: Discussionmentioning

confidence: 99%

“…Age has significant impact on hepatic metabolizing capabilities in humans and animals. This impact on hepatic CYP450 has been reported in a variety of species, such as humans (Saghir et al ., ), pigs (Short & Davis, ; Short et al ., ; Short & Stith, ; Freudenthal et al ., ; Hu, ), cattle (Kawalek & el Said, ), sheep (Kaddouri et al ., ; Flåøyen & Jensen, ; Galtier & Alvinerie, ; Pretheeban et al ., ), horses (Nebbia et al ., ), rats (Warrington et al ., , ), mice (Warrington et al ., , ; Hart et al ., ), and chickens (Hu, ).…”

Section: Introductionmentioning

confidence: 99%

Age‐related change of hepatic uridine diphosphate glucuronosyltransferase and sulfotransferase activities in male chickens and pigs

2016

Vet Pharm & Therapeutics

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The hepatic activities of uridine diphosphate glucuronosyltransferase (UGT) and sulfotransferase (SULT) of male Ross 708 broiler chickens at the age of 1, 7, 14, 28, and 56 days and male Camborough-29 pigs at the age of 1 day and 2, 5, 10, and 20 weeks were investigated. Glucuronidation and sulfation of 4-nitrophenol were used to evaluate the activities. Porcine hepatic UGT and SULT activities were low at birth, peaked at around 5-10 weeks, and then declined. Both hepatic UGT and SULT activities of chickens were high at hatch and declined. Chicken hepatic UGT activity had a peak at the age of 28 days. Affinity of hepatic SULT to 4-nitrophenol is similar in chickens and pigs, but the affinity of hepatic UGT in pigs was about 10 times higher than that in chickens. 4-nitrophenol was predominantly conjugated by SULT instead of UGT in chicken livers from hatch to day 56. Conversely, hepatic UGT contributed predominantly in 4-nitrophenol conjugation than the SULT in pigs from birth to 20 weeks. Therefore, age has significant impact on hepatic activities of UGT and SULT, and the importance of UGT and SULT on conjugation is different in chickens and pigs.

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“…In contrast to men, the ontogeny of CYP450 enzymes in pigs remains largely unknown. Hu (2015) reported in Camborough-29 pigs an increase in average total CYP450 contents in liver microsomes and in biotransformation rate with age for six different substrates (phenacetin, coumarin, tolbutamide, bufuralol, chlorzoxazone, and midazolam) ( Hu, 2015 ). Postnatal maturation of CYP450 enzyme activity in liver microsomes of the Göttingen minipig using four different substrates (phenacetin, tolbutamide, midazolam, and dextromethorphan) was reported by Van Peer et al (2017) .…”

Section: Introductionmentioning

confidence: 99%

The Ontogeny of Cytochrome P450 Enzyme Activity and Protein Abundance in Conventional Pigs in Support of Preclinical Pediatric Drug Research

et al. 2018

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Since the implementation of several legislations to improve pediatric drug research, more pediatric clinical trials are being performed. In order to optimize these pediatric trials, adequate preclinical data are necessary, which are usually obtained by juvenile animal models. The growing piglet has been increasingly suggested as a potential animal model due to a high degree of anatomical and physiological similarities with humans. However, physiological data in pigs on the ontogeny of major organs involved in absorption, distribution, metabolism, and excretion of drugs are largely lacking. The aim of this study was to unravel the ontogeny of porcine hepatic drug metabolizing cytochrome P450 enzyme (CYP450) activities as well as protein abundances. Liver microsomes from 16 conventional pigs (8 males and 8 females) per age group: 2 days, 4 weeks, 8 weeks, and 6–7 months were prepared. Activity measurements were performed with substrates of major human CYP450 enzymes: midazolam (CYP3A), tolbutamide (CYP2C), and chlorzoxazone (CYP2E). Next, the hepatic scaling factor, microsomal protein per gram liver (MPPGL), was determined to correct for enzyme losses during the fractionation process. Finally, protein abundance was determined using proteomics and correlated with enzyme activity. No significant sex differences within each age category were observed in enzyme activity or MPPGL. The biotransformation rate of all three substrates increased with age, comparable with human maturation of CYP450 enzymes. The MPPGL decreased from birth till 8 weeks of age followed by an increase till 6–7 months of age. Significant sex differences in protein abundance were observed for CYP1A2, CYP2A19, CYP3A22, CYP4V2, CYP2C36, CYP2E_1, and CYP2E_2. Midazolam and tolbutamide are considered good substrates to evaluate porcine CYP3A/2C enzymes, respectively. However, chlorzoxazone is not advised to evaluate porcine CYP2E enzyme activity. The increase in biotransformation rate with age can be attributed to an increase in absolute amount of CYP450 proteins. Finally, developmental changes were observed regarding the involvement of specific CYP450 enzymes in the biotransformation of the different substrates.

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Impact of age on hepatic cytochrome P450 of domestic male Camborough‐29 pigs

Cited by 12 publications

References 67 publications

Age-related Differences in CYP3A Abundance and Activity in the Liver of the Göttingen Minipig

Age-related Differences in CYP3A Abundance and Activity in the Liver of the Göttingen Minipig

Age‐related change of hepatic uridine diphosphate glucuronosyltransferase and sulfotransferase activities in male chickens and pigs

The Ontogeny of Cytochrome P450 Enzyme Activity and Protein Abundance in Conventional Pigs in Support of Preclinical Pediatric Drug Research

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