Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA repair-deficient (xeroderma pigmentosum group A (XPA)) and DNA repair-proficient (normal) human skin fibroblasts were genetically engineered by transformation with a controllable human cytochrome P450 (CYP)1A1 expression vector. Induction of CYP1A1 enabled these cells to metabolize (+/-)-benzo[a]pyrene-trans-7,8-dihydrodiol (BPD) into a potent cytotoxicant and mutagen. The XPA cells were more susceptible than the normal cells to the cytotoxic effects of both CYP1A1-metabolized BPD and exogenously supplied (+/-)-anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10- epoxide (BPDE). Furthermore, the differential cytotoxicity between XPA and normal cells induced by CYP1A1-metabolized BPD was 8.4-fold greater than that induced by exogenously supplied BPDE. The two cell lines had similar CYP1A1 activities, suggesting that a difference in metabolic potential was not the cause of the differential response to BPD. At comparable cytotoxicity in both XPA and normal cells, BPD treatment induced more mutants and more DNA adducts than BPDE treatment did. At similar levels of DNA adducts in XPA cells, the levels of cytotoxicity induced by CYP1A1-metabolized BPD and exogenously supplied BPDE were similar, but CYP1A1-metabolized BPD induced a threefold higher hypoxanthine phosphoribosyltransferase mutation frequency. In contrast, at similar levels of adducts in CYP1A1-expressing normal cells, BPD induced less cytotoxicity and a lower mutation frequency. DNA adducts were identified and quantified by 32P-postlabeling analyses. The principal adduct formed by both CYP1A1-metabolized BPD and exogenously supplied BPDE was 10-beta-(deoxyguanosin-N2-yl)-7 beta,8 alpha,9 alpha-trihydroxy-7,8,9,10- tetrahydrobenzo[a]pyrene, indicating that the differential effects of BPD- and BPDE-induced adducts were not due to a difference in the types of adducts formed. The results of these studies suggest that CYP1A1-metabolized BPD may form adducts preferentially in transcriptionally active genes or that the intracellular concentration of BPDE may influence the balance between cytotoxicity and mutagenicity (or both).
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PMID:Differential mutagenicity and cytotoxicity of (+/-)-benzo[a]pyrene-trans-7,8-dihydrodiol and (+/-)-anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide in genetically engineered human fibroblasts. 766 21

UVB and UVC toxicity was detected in Chinese Hamster Ovary (CHO) cell lines AA8, UV5 and XEM2 (a V79-derived cell line expressing rat P450 1A1). Unlike FICZ-HPLC assay that showed induction of CYP1A1 enzyme activity after 20 minutes and 2 hour UVC exposure, the EROD assay showed no difference in cytochrome P450 1A1 (CYP1A1) activity after exposure to different doses of UVB and UVC light. Different cytotoxic and mutagenic effect of photo lesions induced by UVC and UVB light was investigated with the DRAG and HPRT assays, comparing the wild type cell line AA8 and the Nucleotide Excision Repair (NER) deficient cell line UV5. DRAG assay showed a significant difference in UV induced cytotoxicity between UVC and UVB reflecting the larger energy and toxic effect of UVC along with significant difference in UV induced toxicity between AA8 and UV5 cell lines. This was further validated through the HPRT assay, which also showed a significant difference in UVC (5 J/m(2)) induced mutagenic effect between these cell lines. In addition, HPRT assay showed the mutagenic effect of photosensitizer, acetophenone. These results show that UVB and UVC generate serious damage through photo products on DNA, and might induce the metabolic activity of CYP1A1.
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PMID:Cellular and genomic toxicity produced by UV light in Chinese hamster ovary cells. 2457 18