Comparison of rat and human cytochrome P450 (CYP) sources of<i>N</i>-alkylprotoporphyrin IX. Formation after interaction with porphyrinogenic xenobiotics: studies with cDNA-expressed single CYP enzymes

Gamble, Jeremy T.; Nakatsu, Kanji; Marks, Gerald S.

doi:10.1080/0049825021000012637

Cited by 4 publications

(2 citation statements)

References 7 publications

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“…This approach showed that AIA is prone to alkylate rat CYP1A2 but not its human counterpart. Similarly, TTMS forms N-alkylPP when incubated with rat CYP1A2, 2C6, and 2C11, not with the human orthologs 1A2, 2C9, and 2C19 (Gamble et al, 2002). In the present work, CYP2B11 was the only dog CYP isoform able to oxidize the butyramide side-chain of compound 1.…”

Section: Discussionsupporting

confidence: 39%

N-Alkylprotoporphyrin Formation and Hepatic Porphyria in Dogs After Administration of a New Antiepileptic Drug Candidate: Mechanism and Species Specificity

Nicolas

Chanteux

Mancel

et al. 2014

Toxicological Sciences

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A new antiepileptic synaptic vesicle 2a (SV2a) ligand drug candidate was tested in 4-week oral toxicity studies in rat and dog. Brown pigment inclusions were found in the liver of high-dose dogs. The morphology of the deposits and the accompanying liver changes (increased plasma liver enzymes, increased total hepatic porphyrin level, decreased liver ferrochelatase activity, combined induction, and inactivation of cytochrome P-450 CYP2B11) suggested disruption of the heme biosynthetic cascade. None of these changes was seen in rat although this species was exposed to higher parent drug levels. Toxicokinetic analysis and in vitro metabolism assays in hepatocytes showed that dog is more prone to oxidize the drug candidate than rat. Mass spectrometry analysis of liver samples from treated dogs revealed an N-alkylprotoporphyrin adduct. The elucidation of its chemical structure suggested that the drug transforms into a reactive metabolite which is structurally related to a known reference porphyrogenic agent allylisopropylacetamide. That particular metabolite, primarily produced in dog but neither in rat nor in human, has the potential to alkylate the prosthetic heme of CYP. Overall, the data suggested that the drug candidate should not be porphyrogenic in human. This case study further exemplifies the species variability in the susceptibility to drug-induced porphyria.

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Section: Discussionsupporting

confidence: 39%

N-Alkylprotoporphyrin Formation and Hepatic Porphyria in Dogs After Administration of a New Antiepileptic Drug Candidate: Mechanism and Species Specificity

Nicolas

Chanteux

Mancel

et al. 2014

Toxicological Sciences

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show abstract

“…It also plays a role in the pathogenesis of several diseases in which enzyme activity varies from optimum, too high or too low. This may be a result of genetic polymorphism due to an inherited unfavorable set of alleles, mutation of the enzyme encoding gene, effects of chemical substances on the CYP system or, finally, coincidence of the above factors (CLARKE 1998;GAMBLE et al 2002;IBA et al 1999).…”

mentioning

confidence: 99%

The Effect of TCDD Dioxin on the Rat Liver in Biochemical and Histological Assessment

Czepiel¹,

Biesiada²,

Gajda³

et al. 2009

folia biol (krakow)

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Eighteen male Wistar rats were divided into 3 groups of 6 animals each. Two groups received different intraperitoneal doses of TCDD (0.75 and 8Fg) in DMSO solution and the third group (control) received only DMSO on days 0, 7 and 14. On day 21 the animals were sacrificed, and then blood tests, pathological examination and CYP1A1 activity measurement were performed. In rats that received a high dose of dioxin (8 Fg) hepatic lobules revealed parenchymal degeneration and vacuolization of hepatocytes was observed, and also an increased CYP reaction was found in central parts of lobules, around the central vein. The reaction in control and low dose groups was weak. The resorufin level was significantly (P<0.05) higher in the group receiving a low dose of dioxin as compared to the control group. The study confirmed that TCDD damages the rat liver in a dose-dependent manner. Administration of high TCDD doses causing major liver damage also damaged CYP1A1 (based on higher resorufin levels in epiluminescence). TCDD activates CYP1A1, which was confirmed by increased immunohistochemical reactivity of central areas of hepatic lobules.

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The association between chemical-induced porphyria and hepatic cancer

Smith

Foster²

2018

Toxicology Research

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The haem biosynthetic pathway is of fundamental importance for cellular metabolism both for the erythroid and nonerythroid tissues. There are several genetic variants of the pathway in the human population that cause dysfunction of one or other of the enzymes resulting in porphyrias of varying severity. Serious chronic hepatic and systemic diseases may result. Some of these can be precipitated by exposure to drugs including hormones, barbiturates and antibiotics, as well as alcohol and particular chlorinated aromatic chemicals. In experimental animals some of the steps of this pathway can also be severely disrupted by a variety of environmental chemicals, potential drugs and pesticides, especially in the liver, leading to the accumulation of uroporphyrins derived from the intermediate uroporphyrinogens or protoporphyrin IX, the immediate precursor of haem. With some of these chemicals this also leads to cholestasis and liver cell injury and eventually hepatic tumours. The review evaluates the available evidence linking hepatic porphyria with carcinogenesis in naturally occurring human genetic conditions and in chemically-induced porphyrias in laboratory animals. The existing data showing gender, strain, and species differences in sensitivity to the chemical-induced porphyrias, liver injury and liver tumours are discussed and the role that transgenically altered mouse models have played in defining the varying mechanisms. Finally, the review proposes a novel, unifying hypothesis linking the hepatotoxicity induced by the accumulation of various porphyrins, with the increased risk of developing hepatic cancer as a long term consequence.

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Comparison of rat and human cytochrome P450 (CYP) sources ofN-alkylprotoporphyrin IX. Formation after interaction with porphyrinogenic xenobiotics: studies with cDNA-expressed single CYP enzymes

Cited by 4 publications

References 7 publications

N-Alkylprotoporphyrin Formation and Hepatic Porphyria in Dogs After Administration of a New Antiepileptic Drug Candidate: Mechanism and Species Specificity

N-Alkylprotoporphyrin Formation and Hepatic Porphyria in Dogs After Administration of a New Antiepileptic Drug Candidate: Mechanism and Species Specificity

The Effect of TCDD Dioxin on the Rat Liver in Biochemical and Histological Assessment

The association between chemical-induced porphyria and hepatic cancer

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