Table 8.
Phase I and phase II metabolites of AOH and AME
| Metabolic reaction | Metabolite of AOH | Metabolite of AME | Enzyme isoform | References |
|---|---|---|---|---|
| Demethylation | - | alternariol (AOH) | Rat liver post-mitochondrial supernatant with NADPH | Pollock et al. (1982) |
| Adult male Sprague Dawley rats (detected in urine and feces) | ||||
| Homogenized liver samples of gilts with NADPH | Olsen and Visconti (1988) | |||
| Rat, pig, and human liver microsomes with NADPH | Pfeiffer et al. (2007) | |||
| Hydroxylation | 2-hydroxy-alternariol (2-OH-AOH) | 2-hydroxy-alternariol monomethyl ether (2-OH-AME) | Rat, pig, and human liver microsomes with NADPH | Pfeiffer et al. (2007) |
| Precision-cut liver slices | Burkhardt et al. (2011) | |||
| - | Male and female NMRI mice (detected in blood) | Schuchardt et al. (2014) | ||
| 4-hydroxy-alternariol (4-OH-AOH) | 4-hydroxy-alternariol monomethyl ether (4-OH-AME) | Rat, pig, and human liver microsomes with NADPH | Pfeiffer et al. (2007) | |
| Precision-cut rat liver slices | Burkhardt et al. (2011) | |||
| - | Male and female NMRI mice (detected in blood) | Schuchardt et al. (2014) | ||
| Male Sprague Dawley rats (detected in feces) | Puntscher et al. (2019a) | |||
| 8-hydroxy-alternariol (8-OH-AOH) | 8-hydroxy-alternariol monomethyl ether (8-OH-AME) | Rat, pig, and human liver microsomes with NADPH | Pfeiffer et al. (2007) | |
| Precision-cut liver slices | Burkhardt et al. (2011) | |||
| 10-hydroxy-alternariol (10-OH-AOH) | 10-hydroxy-alternariol monomethyl ether (10-OH-AME) | Rat, pig and human liver microsomes with NADPH | Pfeiffer et al. (2007) | |
| Precision-cut rat liver slices | Burkhardt et al. (2011) | |||
| - | Male and female NMRI mice (detected in blood) | Schuchardt et al. (2014) | ||
| dihydroxy-alternariol monomethyl ether ((OH)2-AME) | - | Rat, pig, and human liver microsomes with NADPH | Pfeiffer et al. (2007) | |
| Methylation and hydroxylation | methyl-hydroxy-alternariol (Me-OH-AOH) | methyl-hydroxy-alternariol monomethyl ether (Me-OH-AME) | Rat, pig, and human liver microsomes with NADPH | Pfeiffer et al. (2007) |
| Incubation of purified hydroxy metabolites with rat liver cytosol and SAM | Burkhardt et al. (2011) | |||
| Glucuronidation | alternariol-3-O-glucuronide (AOH-3-O-GlcA) | alternariol monomethyl ether-3-O-glucuronide (AME-3-O-GlcA) | Caco-2 cell line | Burkhardt et al. (2009) |
| Hepatic and intestinal microsomes of humans, pigs and rats with UDPGA | Pfeiffer et al. (2009b) | |||
| - | alternariol monomethyl ether-7-O-glucuronide (AME-7-O-GlcA) | Caco-2 cell line | Burkhardt et al. (2009) | |
| Liver and intestinal microsomes of humans, pigs and rats with UDPGA | Pfeiffer et al. (2009b) | |||
| alternariol-9-O-glucuronide (AOH-9-O-GlcA) | - | Caco-2 cell line | Burkhardt et al. (2009) | |
| Hepatic and intestinal microsomes of humans, pigs and rats with UDPGA | Pfeiffer et al. (2009a) | |||
| - | alternariol monomethyl ether glucuronides | Homogenized liver and intestinal samples of gilts with UDPGA | Olsen and Visconti (1988) | |
| Sulfation | alternariol-3-O-sulfate (AOH-3-O-S) | alternariol monomethyl ether-3-O-sulfate (AME-3-O-S) | Caco-2 cell line | Burkhardt et al. (2009) |
| Male Sprague Dawley rats (AOH-3-O-S found in urine, AME-3-O-S detected in urine, plasma, and feces) | Puntscher et al. (2019a) | |||
| Rat liver cytosol with PAPS | Burkhardt et al. (2009) | |||
| alternariol-7-O-sulfate (AOH-7-O-S) | alternariol monomethyl ether-7-O-sulfate (AME-7-O-S) | Rat liver cytosol with PAPS | Burkhardt et al. (2009) | |
| alternariol-9-O-sulfate (AOH-9-O-S) | - | Rat liver cytosol with PAPS | Burkhardt et al. (2009) | |
| Studies performed with single human enzyme isoforms | ||||
| Hydroxylation | 2-hydroxy-alternariol (2-OH-AOH) | 2-hydroxy-alternariol monomethyl ether (2-OH-AME) | CYP isoforms 1A1, 1A2. 1B1, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 | Pfeiffer et al. (2008) |
| - | CYP3A5 | |||
| 4-hydroxy-alternariol (4-OH-AOH) | - | CYP2E1 | ||
| 4-hydroxy-alternariol monomethyl ether (4-OH-AME) | CYP isoforms 1A1, 1A2. 1B1, 2A6, 2C9, 2C19, 2D6, 3A4 | |||
| - | CYP isoforms 2B6, 3A5 | |||
| 8-hydroxy-alternariol (8-OH-AOH) | 8-hydroxy-alternariol monomethyl ether (8-OH-AME) | CYP isoforms 1A2, 2C19, 2D6, 2E1, 3A4 | ||
| - | CYP isoforms 1A1, 1B1, 2A6, 2B6, 3A5 | |||
| 10-hydroxy-alternariol (10-OH-AOH) | 10-hydroxy-alternariol monomethyl ether (10-OH-AME) | CYP3A4 | ||
| - | CYP isoforms 1A1, 3A5 | |||
| Glucuronidation | alternariol-3-O-glucuronide (AOH-3-O-GlcA) | alternariol monomethyl ether-3-O-glucuronide (AME-3-O-GlcA) | UGT isoforms 1A1, 1A3, 1A7, 1A8, 1A9, 1A10, 2B7, 2B15 | Pfeiffer et al. (2009a) |
| - | UGT1A6 | |||
| alternariol-9-O-glucuronide (AOH-9-O-GlcA) | - | UGT isoforms 1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, 2B15 | ||
| - | alternariol monomethyl ether-7-O-glucuronide (AME-7-O-GlcA) | UGT isoforms 1A1, 1A3, 1A7, 1A8, 1A9, 1A10 | ||