Abstract
During the cooking of meats, several highly mutagenic heterocyclic amines (HCAs) are produced. Three HCAs, IQ, MeIQx, and PhIP have been under study for carcinogenicity in cynomolgus monkeys, and to date, IQ has been shown to be a potent hepatocarcinogen. Concomitantly, the metabolic processing of these HCAs has been examined. Metabolism studies show that the potent hepatocarcinogenicity of IQ is associated with the in vivo metabolic activation of IQ via N-hydroxylation and the formation of DNA adducts. In monkeys undergoing carcinogen bioassay with IQ, N-hydroxylation was confirmed by the presence of the N-hydroxy-N-glucuronide conjugate of IQ in urine. The N-hydroxylation of IQ appears to be carried out largely by hepatic CYP3A4 and/or CYP2C9/10, and not by CYP1A2, an isoform not expressed in liver of this species. Notably MeIQx is poorly activated in cynomolgus monkeys and lacks the potency of IQ to induce hepatocellular carcinoma after a 5-year dosing period. The poor activation of MeIQx appears to be due to the lack of constitutive expression of CYP1A2 and an inability of other cytochromes P450, such as CYP3A4 and CYP2C9/10, to N-hydroxylate the quinoxalines. MeIQx is detoxified in monkeys largely by conjugation with glucuronide at the N-1 position. Although the carcinogenicity of PhIP is not yet known,the metabolic data suggest that PhIP will be carcinogenic in this species. PhIP is metabolically activated in vivo in monkeys by N-hydroxylation, as discerned by the presence of the N-hydroxy-N-glucuronide conjugate in urine, bile, and plasma. PhIP also produces DNA adducts that are widely distributed in tissues. The results from these studies support the importance of N-hydroxylation in the carcinogenicity of HCAs in nonhuman primates and by analogy, the importance of this metabolic activation step in the possible carcinogenicity of dietary HCAs in humans.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 203-210 |
| Number of pages | 8 |
| Journal | Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis |
| Volume | 376 |
| Issue number | 1-2 |
| DOIs | |
| State | Published - May 12 1997 |
| Externally published | Yes |
Fingerprint
Keywords
- DNA adducts
- Food carcinogen
- IQ
- MeIQx
- Metabolism
- PhIP
ASJC Scopus subject areas
- Health, Toxicology and Mutagenesis
- Molecular Biology
Cite this
Metabolism of food-derived heterocyclic amines in nonhuman primates. / Snyderwine, Elizabeth G.; Turesky, Robert J.; Turteltaub, Ken W; Davis, Cindy D.; Sadrieh, Nakissa; Schut, Herman A J; Nagao, Minako; Sugimura, Takashi; Thorgeirsson, Unnur P.; Adamson, Richard H.; Thorgeirsson, Snorri S.
In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 376, No. 1-2, 12.05.1997, p. 203-210.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Metabolism of food-derived heterocyclic amines in nonhuman primates
AU - Snyderwine, Elizabeth G.
AU - Turesky, Robert J.
AU - Turteltaub, Ken W
AU - Davis, Cindy D.
AU - Sadrieh, Nakissa
AU - Schut, Herman A J
AU - Nagao, Minako
AU - Sugimura, Takashi
AU - Thorgeirsson, Unnur P.
AU - Adamson, Richard H.
AU - Thorgeirsson, Snorri S.
PY - 1997/5/12
Y1 - 1997/5/12
N2 - During the cooking of meats, several highly mutagenic heterocyclic amines (HCAs) are produced. Three HCAs, IQ, MeIQx, and PhIP have been under study for carcinogenicity in cynomolgus monkeys, and to date, IQ has been shown to be a potent hepatocarcinogen. Concomitantly, the metabolic processing of these HCAs has been examined. Metabolism studies show that the potent hepatocarcinogenicity of IQ is associated with the in vivo metabolic activation of IQ via N-hydroxylation and the formation of DNA adducts. In monkeys undergoing carcinogen bioassay with IQ, N-hydroxylation was confirmed by the presence of the N-hydroxy-N-glucuronide conjugate of IQ in urine. The N-hydroxylation of IQ appears to be carried out largely by hepatic CYP3A4 and/or CYP2C9/10, and not by CYP1A2, an isoform not expressed in liver of this species. Notably MeIQx is poorly activated in cynomolgus monkeys and lacks the potency of IQ to induce hepatocellular carcinoma after a 5-year dosing period. The poor activation of MeIQx appears to be due to the lack of constitutive expression of CYP1A2 and an inability of other cytochromes P450, such as CYP3A4 and CYP2C9/10, to N-hydroxylate the quinoxalines. MeIQx is detoxified in monkeys largely by conjugation with glucuronide at the N-1 position. Although the carcinogenicity of PhIP is not yet known,the metabolic data suggest that PhIP will be carcinogenic in this species. PhIP is metabolically activated in vivo in monkeys by N-hydroxylation, as discerned by the presence of the N-hydroxy-N-glucuronide conjugate in urine, bile, and plasma. PhIP also produces DNA adducts that are widely distributed in tissues. The results from these studies support the importance of N-hydroxylation in the carcinogenicity of HCAs in nonhuman primates and by analogy, the importance of this metabolic activation step in the possible carcinogenicity of dietary HCAs in humans.
AB - During the cooking of meats, several highly mutagenic heterocyclic amines (HCAs) are produced. Three HCAs, IQ, MeIQx, and PhIP have been under study for carcinogenicity in cynomolgus monkeys, and to date, IQ has been shown to be a potent hepatocarcinogen. Concomitantly, the metabolic processing of these HCAs has been examined. Metabolism studies show that the potent hepatocarcinogenicity of IQ is associated with the in vivo metabolic activation of IQ via N-hydroxylation and the formation of DNA adducts. In monkeys undergoing carcinogen bioassay with IQ, N-hydroxylation was confirmed by the presence of the N-hydroxy-N-glucuronide conjugate of IQ in urine. The N-hydroxylation of IQ appears to be carried out largely by hepatic CYP3A4 and/or CYP2C9/10, and not by CYP1A2, an isoform not expressed in liver of this species. Notably MeIQx is poorly activated in cynomolgus monkeys and lacks the potency of IQ to induce hepatocellular carcinoma after a 5-year dosing period. The poor activation of MeIQx appears to be due to the lack of constitutive expression of CYP1A2 and an inability of other cytochromes P450, such as CYP3A4 and CYP2C9/10, to N-hydroxylate the quinoxalines. MeIQx is detoxified in monkeys largely by conjugation with glucuronide at the N-1 position. Although the carcinogenicity of PhIP is not yet known,the metabolic data suggest that PhIP will be carcinogenic in this species. PhIP is metabolically activated in vivo in monkeys by N-hydroxylation, as discerned by the presence of the N-hydroxy-N-glucuronide conjugate in urine, bile, and plasma. PhIP also produces DNA adducts that are widely distributed in tissues. The results from these studies support the importance of N-hydroxylation in the carcinogenicity of HCAs in nonhuman primates and by analogy, the importance of this metabolic activation step in the possible carcinogenicity of dietary HCAs in humans.
KW - DNA adducts
KW - Food carcinogen
KW - IQ
KW - MeIQx
KW - Metabolism
KW - PhIP
UR - http://www.scopus.com/inward/record.url?scp=0342929506&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0342929506&partnerID=8YFLogxK
U2 - 10.1016/S0027-5107(97)00044-4
DO - 10.1016/S0027-5107(97)00044-4
M3 - Article
C2 - 9202757
AN - SCOPUS:0342929506
VL - 376
SP - 203
EP - 210
JO - Mutation Research
JF - Mutation Research
SN - 0027-5107
IS - 1-2
ER -