Mechanisms of 3-methylindole pneumotoxicity

Yost, Garold S.

doi:10.1021/tx00011a001

Cited by 77 publications

(52 citation statements)

References 34 publications

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“…Hence, no pulmonary lesions were found at autopsy. These observations imply a difference in species sensitivity between pigs and ruminants, as already reported for rodents and ruminants (Yost 1989). Furthermore, the dosage administered to the goats was 10-to 100-fold larger than those given to the pigs, which could be of importance due to the reported pneumotoxic effects of 3MI (Bray and Carlson 1979).…”

Section: Discussionsupporting

confidence: 60%

The effect of peroral and intracaecal 3-methylindole administration on the quantitative absorption to the portal vein in growing intact male pigs

Laue¹,

Hansen-Møller²,

Agergaard³

1998

Can. J. Anim. Sci.

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Laue, A., Hansen-Møller, J. and Agergaard, N. 1998. The effect of peroral and intracaecal 3-methylindole administration on the quantitative absorption to the portal vein in growing intact male pigs. Can. J. Anim. Sci. 78: 69-79. This study intends to extend knowledge on the fate of intestinal 3-methylindole (3MI) in vivo as the substance is a key causative agent in the expression of boar taint in pig carcasses. Eleven multi-catheterized and caecum-fistulated intact male pigs were used to examine the effects of peroral and intracaecal challenges of 1, 5 and 10 mg 3-methylindole per kilogram body weight (BW) on the quantitative net absorption from specific sites of the alimentary canal (AC), measured as 3MI portal net appearance (PNA). Faeces were collected once a day while portal, hepatic and jugular vein as well as arterial blood were collected during the experiments lasting 300 min. Portal blood flow was recorded by ultrasonic blood flow probes. The BW of the pigs averaged 73 to 89 kg at the beginning and end of the experiments. All pigs on the untreated control treatment absorbed 3MI from the AC. Faecal 3MI concentrations did not differ between control and 3MI-treated pigs. On the other hand, an evident difference was observed in the PNA between the controls with an average of 11.2 mg 3MI (300 min) -1 and 3MI-treated animals varying from 23.9 to 308 mg 3MI (300 min) -1 . After application of 3MI, the net absorption from the AC to the portal blood plasma increased up to 147 times. Depending on the site of administration and the dosage application, plasma peak values of 3MI occurred within the first 30 min after the challenge. Within the doses of 1 to 10 mg 3MI (kg BW) -1 , no absorption plateau was to be reached. The observed rapid absorption of 3MI leads to the assumption that the mechanism is mainly by passive diffusion. Intravenous 3MI injections indicated diffusion from the blood circulation to the intestinal lumen. The site of administering exogenous 3MI was of less importance for the PNA than the dosage applied. This implies that the permeability for 3MI along the AC is identical, no matter where it is introduced. Results indicate a proportional relation between the 3MI dosage administered and the PNA. Finally, it was observed that a) pigs with high (pre-experimental) initial PNAs subsequently also absorbed more 3MI after challenges of additional 3MI, expressed as PNAs; and b) pigs with increasing BW exhibited higher PNAs, indicating a rise of 3MI absorption with advancing age. Le 3MI est la substance principale responsable de l'expression de l'odeur sexuelle dans les carcasses de porcs. Onze jeunes verrats entiers portant de multiples cathéters ainsi qu'une fistule caecale étaient utilisés pour examiner les effets d'injections tests de 1, 5 et de 10 mg de 3-méthylindole par kilo de poids corporel (PC) sur l'absorption quantitative nette dans différentes parties du tractus digestif (TD) mesurée d'après le taux d'apparition net de 3MI dans le plasma sanguin de la veine porte (ANP). Les fèces étaient prélev...

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Section: Discussionsupporting

confidence: 60%

The effect of peroral and intracaecal 3-methylindole administration on the quantitative absorption to the portal vein in growing intact male pigs

Laue¹,

Hansen-Møller²,

Agergaard³

1998

Can. J. Anim. Sci.

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“…The level of skatole intestinal production is mainly dependent on nutritional factors [18] and no genetic control has been demonstrated so far. This compound is a pneumotoxin in several mammalian species including goats, cattle and man [52] but not in pigs. No physiological function of skatole is known in pigs.…”

Section: Genes Involved In the Metabolism Of Skatolementioning

confidence: 99%

Genetic and metabolic aspects of androstenone and skatole deposition in pig adipose tissue: A review(Open Access publication)

Robic

Larzul²,

Bonneau³

2007

Genet. Sel. Evol.

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-High levels of androstenone and skatole in fat tissues are considered the primary causes of boar taint, an unpleasant odour and flavour of the meat from non-castrated male pigs. The aim of this article is to review our current knowledge of the biology and genetic control of the accumulation of androstenone and skatole in fat tissue. Two QTL mapping studies have shown the complexity of the genetic control of these traits. During the last ten years, several authors have taken a more physiological approach to investigate the involvement of genes controlling the metabolism of androstenone and skatole. Although some authors have claimed the identification of candidate genes, it is more appropriate to talk about target genes. This suggests that genes affecting androstenone and skatole levels will have to be sought for among specific or non-specific transcription factors interacting with these target genes.androstenone / skatole / pig / boar taint / QTL

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“…3-MI 18, known to cause pulmonary toxicity in livestock (Yost, 1989), induced unspecific toxicity in all cells already at 29 µM, although cells expressing r-P422, h-P + 12 and to a lesser extent h-P427 displayed a higher death rate (Fig. 2H) suggesting that CYP4B1 is involved in the conversion of 3-MI 18.…”

Section: Cytotoxicity Assay In Human Cellsmentioning

confidence: 96%

Ligand characterization of CYP4B1 isoforms modified for high-level expression inEscherichia coliand HepG2 cells

Roellecke

Jäger

Gyurov

et al. 2017

Protein Engineering, Design and Selection

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Human CYP4B1, a cytochrome P450 monooxygenase predominantly expressed in the lung, inefficiently metabolizes classical CYP4B1 substrates, such as the naturally occurring furan pro-toxin 4-ipomeanol (4-IPO). Highly active animal forms of the enzyme convert 4-IPO to reactive alkylating metabolite(s) that bind(s) to cellular macromolecules. By substitution of 13 amino acids, we restored the enzymatic activity of human CYP4B1 toward 4-IPO and this modified cDNA is potentially valuable as a suicide gene for adoptive T-cell therapies. In order to find novel pro-toxins, we tested numerous furan analogs in in vitro cell culture cytotoxicity assays by expressing the wildtype rabbit and variants of human CYP4B1 in human liver-derived HepG2 cells. To evaluate the CYP4B1 substrate specificities and furan analog catalysis, we optimized the N-terminal sequence of the CYP4B1 variants by modification/truncation and established their heterologous expression in Escherichia coli (yielding 70 and 800 nmol·l −1 of recombinant human and rabbit enzyme, respectively). Finally, spectral binding affinities and oxidative metabolism of the furan analogs by the purified recombinant CYP4B1 variants were analyzed: the naturally occurring perilla ketone was found to be the tightest binder to CYP4B1, but also the analog that was most extensively metabolized by oxidative processes to numerous non-reactive reaction products.

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Mechanisms of 3-methylindole pneumotoxicity

Cited by 77 publications

References 34 publications

The effect of peroral and intracaecal 3-methylindole administration on the quantitative absorption to the portal vein in growing intact male pigs

The effect of peroral and intracaecal 3-methylindole administration on the quantitative absorption to the portal vein in growing intact male pigs

Genetic and metabolic aspects of androstenone and skatole deposition in pig adipose tissue: A review(Open Access publication)

Ligand characterization of CYP4B1 isoforms modified for high-level expression inEscherichia coliand HepG2 cells

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