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CYP1A2, GSTM1, and GSTT1 polymorphisms and diet effects on CYP1A2 activity in a crossover feeding trial.

ABSTRACT: Cytochrome P-450 1A2 (CYP1A2) is a biotransformation enzyme that activates several procarcinogens. CYP1A2 is induced by cruciferous and inhibited by apiaceous vegetable intake. Using a randomized, crossover feeding trial in humans, we investigated the dose effects of cruciferous vegetables and the effects of any interaction between cruciferous and apiaceous vegetables on CYP1A2 activity. We also investigated whether response varied by CYP1A2*1F, GSTM1, and GSTT1 genotypes (glutathione S-transferases that metabolize crucifer constituents) and whether CYP1A2 activity rebounds after apiaceous vegetables are removed from the diet. Participants (N = 73), recruited based on genotypes, consumed four diets for two weeks each: low-phytochemical diet (basal), basal plus single dose of cruciferous (1C), basal plus double dose of cruciferous (2C), and basal plus single dose of cruciferous and apiaceous vegetables (1C+A). CYP1A2 activity was determined by urine caffeine tests administered at baseline and the end of each feeding period. Compared with basal diet, the 1C diet increased CYP1A2 activity (P < 0.0001) and the 2C diet resulted in further increases (P < 0.0001), with men experiencing greater dose-response than women. The 1C+A diet decreased CYP1A2 activity compared with the 1C and 2C diets (P < 0.0001 for both). Although there was no overall effect of CYP1A2*1F or GSTM1-null/GSTT1-null genotypes or genotype-by-diet interactions, there were significant diet response differences within each genotype. Additionally, CYP1A2 activity recovered modestly one day after the removal of apiaceous vegetables. These results suggest complex interactions among dietary patterns, genetic variation, and modulation of biotransformation that may not be apparent in observational studies.

SUBMITTER: Peterson S

PROVIDER: S-EPMC2784188 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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CYP1A2, GSTM1, and GSTT1 polymorphisms and diet effects on CYP1A2 activity in a crossover feeding trial.

Peterson Sabrina S Schwarz Yvonne Y Li Shuying S SS Li Lin L King Irena B IB Chen Chu C Eaton David L DL Potter John D JD Lampe Johanna W JW

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20091020 11

Cytochrome P-450 1A2 (CYP1A2) is a biotransformation enzyme that activates several procarcinogens. CYP1A2 is induced by cruciferous and inhibited by apiaceous vegetable intake. Using a randomized, crossover feeding trial in humans, we investigated the dose effects of cruciferous vegetables and the effects of any interaction between cruciferous and apiaceous vegetables on CYP1A2 activity. We also investigated whether response varied by CYP1A2*1F, GSTM1, and GSTT1 genotypes (glutathione S-transfer ...[more]

PMID: 19843669

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Project description:Oxidative stress and systemic inflammation are closely linked with increased risk of cancer development. Tumor necrosis factor alpha (TNF-?) is one of the pro-inflammatory cytokines. Glutathione S-transferases (GSTs) are enzymes involved in oxidative stress handling. Polymorphisms of genes encoding mentioned molecules may potentially influence the risk and the outcome in neoplastic diseases. Multiple myeloma (MM) is a hematological malignancy characterized by clonal, atypical plasma cell proliferation. In the present study we investigated the association of deletion polymorphisms in GSTT1/GSTM1 genes and single nucleotide polymorphisms (SNPs) in the TNF-? gene at positions -308/-238 with the risk and outcome in MM and sensitivity to bortezomib under in vitro conditions. One hundred newly diagnosed MM patients and 100 healthy blood donors were genotyped by means of multiplex PCR (for GSTs) and PCR-RFLP (for TNF-?). In a subgroup of 50 MM patients, bone marrow cells were treated with bortezomib in vitro. Patients with -238GA+AA or GSTT1-null genotypes had 2.0 (p = 0.002) or 2.29 (p = 0.013) fold increased risk of MM. The interaction effects and risk of MM were observed in GSTT1/GSTM1-null (OR = 2.82, p = 0.018), -308/-238GA+AA (OR = 5.63, p < 0.001), as well as in all combinations of -308 with GSTs. The -308/-238GA+AA genotypes in comparison to GG were associated with earlier MM onset-61.14 vs. 66.86 years (p = 0.009) and 61.72 vs. 66.52 years (p = 0.035), respectively. Patients with GSTM1-present had shorter progression-free-survival (15.17 vs. 26.81 months, p = 0.003) and overall-survival (22.79 vs. 34.81 months, p = 0.039) compared with GSTM1-null. We did not observe relationship between response rate and studied polymorphisms. The in vitro study revealed significantly higher number of apoptotic cells at 12 nM of bortezomib in GSTT1-present, GSTM1-null/present, -308GG and -238GG/GA+AA genotypes. Our findings comprise large analysis of studied polymorphisms in MM.

Dataset Information

CYP1A2, GSTM1, and GSTT1 polymorphisms and diet effects on CYP1A2 activity in a crossover feeding trial.

Publications

CYP1A2, GSTM1, and GSTT1 polymorphisms and diet effects on CYP1A2 activity in a crossover feeding trial.

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