Interspecies metabolism of heterocyclic aromatic amines and the uncertainties in extrapolation of animal toxicity data for human risk assessment

Turesky, Robert J.

doi:10.1002/mnfr.200400076

Cited by 47 publications

(36 citation statements)

References 153 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Human/rodent CYP1A2 orthologs are well known to exhibit species-specific differences in the rates by which various substrates are metabolized [11]. For example, human and mouse CYP1A2 differ by 3-to 7-fold in catalyzing ethoxyresorufin O-deethylation [12] and uroporphyrinogen oxidation [13].…”

Section: Cyp1a1(−/−)mentioning

confidence: 99%

Generation of ‘humanized’ hCYP1A1_1A2_Cyp1a1/1a2(−/−) mouse line

Dragin

Uno

Wang

et al. 2007

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Human/rodent CYP1A1 and CYP1A2 orthologs are well known to exhibit species-specific differences in substrate preferences and rates of metabolism. This lab previously characterized a BAC-transgenic mouse carrying the human CYP1A1_CYP1A2 locus; in this line, human dioxininducible CYP1A1 and basal vs dioxin-inducible CYP1A2 have been shown to be expressed normally (with regard to mRNAs, proteins and three enzyme activities) in every one of nine mouse tissues studied. The mouse Cyp1a1 and Cyp1a2 genes are oriented head-to-head and share a bidirectional promoter region of 13,954 bp. Using Cre recombinase and loxP sites inserted 3′ of the stop codons of both genes, we show here a successful interchromosomal excision of 26,173 bp that ablated both genes on the same allele. The Cyp1a1/1a2(−) double-knockout allele was bred with the "humanized" line; the final product is the hCYP1A1_1A2_Cyp1a1/1a2(−/−) line on a theoretically >99.8% C57BL/6J genetic background-having both human genes replacing the mouse orthologs. This line will be valuable for human risk assessment studies involving any environmental toxicant or drug that is a substrate for CYP1A1 or CYP1A2. KeywordsHumanized mouse line; Human CYP1A1_1A2 locus; Mouse Cyp1a1_1a2 locus; loxP; Cre recombinase; Interchromosomal excision; Benzo [a]pyrene; DioxinThe human and mouse cytochrome P450 (CYP) gene superfamilies contain 57 and 102 proteincoding genes, respectively; one of the 18 mammalian CYP families is CYP1, having three members in both human and mouse-CYP1A1, CYP1A2, and CYP1B1 [1][2][3]. The CYP1A and CYP1B subfamily ancestors diverged from one another probably more than 500 million years ago; CYP1A2 arose as a gene duplication event from CYP1A1 about 450 million years ago. Thus, land animals (including fowl) carry both CYP1A1 and CYP1A2; sea animals do not have the CYP1A2 gene [4]. Accordingly, the CYP1A1 and CYP1A2 genes are located at human chromosome 15q24.1, in head-to-head orientation, 23,306 bases from one transcription initiation start-site to the other [5]. Of three mammalian genomes studied, estimates are that about 10% of gene duplication pairs share bidirectional promoters [6]. The latest data from the UCSC browser assembled by NCBI and the Mouse Genome Sequencing Consortium puts the Cyp1a1 and Cyp1a2 genes on mouse chromosome 9 at cM 31.0, also in a head-to-head orientation, 13,954 bases from one transcription start-site to the other. In contrast, CYP1B1 is located on human chromosome 2p22.2, and Cyp1b1 (syntenic with human CYP1B1) is located on mouse chromosome 17. Using bacterial artificial chromosomes (BACs), we and others have been able to generate "humanized" hCYP1A1_1A2 BAC-transgenic lines [5,14]. Studies have been carried out with the hCYP1A1_1A2_Cyp1a1(−/−) line vs the hCYP1A1_1A2_Cyp1a2(−/−) line; for example, these lines were used both for theophylline [15] and for the food mutagen 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) [14]. In both cases, human CYP1A2 was shown to be responsible for the "human metabolite profile...

show abstract

Section: Cyp1a1(−/−)mentioning

confidence: 99%

Generation of ‘humanized’ hCYP1A1_1A2_Cyp1a1/1a2(−/−) mouse line

Dragin

Uno

Wang

et al. 2007

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

show abstract

“…Identification of mutagenic substances associated with cooking of high fat diet has been the object of many efforts. Pyrolysis of aromatic amino-acids and of fatty acids associated with grilled meat has been suspected to be involved in mutagenesis, leading to the hypothesis that heterocyclic aromatic amines (HAAs) and polycyclic aromatic hydrocarbons (PAH) respectively could play a role in cancer initiation (36)(37)(38). Some epidemiological studies support this hypothesis, whereas others do not.…”

Section: ------------------------------------------------Smoking-relamentioning

confidence: 99%

The growing incidence of cancer: Role of lifestyle and screening detection (Review)

Belpomme¹,

Irigaray²,

Sasco³

et al. 2007

Int J Oncol

View full text Add to dashboard Cite

Abstract. The increasing incidence of a variety of cancers after the Second World War confronts scientists with the question of their origin. In Western countries, expansion and ageing of the population, as well as progress in cancer detection using new diagnostic and screening tests cannot fully account for the observed growing incidence of cancer. Our hypothesis is that environmental factors play a more important role in cancer genesis than it is usually agreed: i) over the last 2-3 decades, alcohol consumption and tobacco smoking in men have significantly decreased; ii) obesity is increasing in many countries, but the growing incidence of cancer also concerns cancers not related to obesity nor to other lifestyle-related factors; iii) there is evidence that the environment has changed over the same time scale as the recent rise in cancer incidence, and that this change included the accumulation of many new carcinogenic factors in the environment; iv) genetic susceptibility to cancer due to genetic polymorphism cannot have changed over one generation and actually favours the role of exogenous factors through geneenvironment interactions; v) age is not the unique factor to be considered since the rising incidence of cancers is seen across all age categories, including children; vi) the fetus is specifically vulnerable to exogenous factors. A fetal exposure during a critical window period may explain why current epidemiological studies may be negative in adults. We therefore propose that the involuntary exposure to many carcinogens in the environment contributes to the rising trend in cancer incidence.

show abstract

“…Aromatic amines require a two-stage metabolic activation before they can react with DNA (1,13,14). A cytochrome P450 oxidizes the aromatic amine to a hydroxylamine, which is subsequently esterified by N-acetyltransferase or sulfotrans-ferase.…”

Section: Introductionmentioning

confidence: 99%

Conformational Differences of the C8-Deoxyguanosine Adduct of 2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) within the NarI Recognition Sequence

Elmquist

Wang

Stover

et al. 2007

Chem. Res. Toxicol.

View full text Add to dashboard Cite

Abstract2-Amino-3-methylimidazo [4,5-f]quinoline (IQ) is a highly mutagenic heterocyclic amine found in cooked meats. The major DNA adduct of IQ is at the C8-position of dGuo. We have previously reported the incorporation of the C8-IQ adduct into oligonucleotides, namely, the G 1 -position of codon 12 of the N-ras oncogene sequence (G 1 G 2 T) and the G 3 -position of the NarI recognition sequence (G 1 G 2 CG 3 CC) (Elmquist et al. (2004) J. Am. Chem. Soc. 126, 11189-11201). Ultraviolet spectroscopy and circular dichroism studies indicated that the conformation of the adduct in the two oligonucleotides was different, and they were assigned as groove-bound and base-displaced intercalated, respectively. The conformation of the latter was subsequently confirmed through NMR and restrained molecular dynamics studies (Wang et al. (2006) J. Am. Chem. Soc. 128, 10085-10095). We report here the incorporation of the C8-IQ adduct into the G 1 -and G 2 -positions of the NarI sequence. A complete analysis of the UV, CD, and NMR chemical shift data for the IQ protons are consistent with the IQ adduct adopting a minor groove-bound conformation at the G 1 -and G 2 -positions of the NarI sequence. To further correlate the spectroscopic data with the adduct conformation, the C8-aminofluorene (AF) adduct of dGuo was also incorporated into the NarI sequence; previous NMR studies demonstrated that the AF-modified oligonucleotides were in a sequence-dependent conformational exchange between major groove-bound and base-displaced intercalated conformations. The spectroscopic data for the IQ-and AF-modified oligonucleotides are compared. The sequence-dependent conformational preferences are likely to play a key role in the repair and mutagenicity of C8-arylamine adducts.

show abstract

Interspecies metabolism of heterocyclic aromatic amines and the uncertainties in extrapolation of animal toxicity data for human risk assessment

Cited by 47 publications

References 153 publications

Generation of ‘humanized’ hCYP1A1_1A2_Cyp1a1/1a2(−/−) mouse line

Generation of ‘humanized’ hCYP1A1_1A2_Cyp1a1/1a2(−/−) mouse line

The growing incidence of cancer: Role of lifestyle and screening detection (Review)

Conformational Differences of the C8-Deoxyguanosine Adduct of 2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) within the NarI Recognition Sequence

Contact Info

Product

Resources

About