Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytochrome P450 1A1 (CYP1A1) activity is associated with increased susceptibility to lung cancer induced by polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BP). In non-hepatic human tissues, CYP1A1 is the principal enzyme responsible for the metabolic activation of the proximate BP mutagenic metabolite, (-)-benzo[a]pyrene-trans-7,8-dihydrodiol, to (+)-anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide, the ultimate BP mutagen. We have genetically engineered both DNA repair-deficient (xeroderma pigmentosum group A) and DNA repair-proficient human skin fibroblasts to express human CYP1A1 under control of the inducible mouse metallothionein-I promoter. CYP1A1 activity was induced by CdSO4 and monitored by following the O-deethylation of ethoxy fluorescein ethyl ester or of 7-ethoxyresorufin. Induced CYP1A1 activities were similar in both cell lines and were dependent on CdSO4 concentration and induction time. Maximal CYP1A1 activities were obtained in 4-6 h with 5-7 microM CdSO4. BPD-induced cytotoxicity and hypoxanthine phosphoribosyl transferase mutagenicity were both quantitatively correlated with the level of CYP1A1 activity and were greater in DNA repair-deficient cells than in DNA repair-proficient cells. The results suggest that modestly induced CYP1A1 activity is a risk factor in polycyclic aromatic hydrocarbon-induced carcinogenesis.
 ...
PMID:Cytotoxicity and genotoxicity of (+/-)-benzo[a]pyrene-trans-7,8-dihydrodiol in CYP1A1-expressing human fibroblasts quantitatively correlate with CYP1A1 expression level. 792 75

Cytochromes P450 catalyze the bioactivation of many carcinogens. In particular, cytochrome P450 1A1 (CYP1A1) catalyzes the conversion of polycyclic aromatic hydrocarbons, such as benzo[a]pyrene, into potent mutagenic agents. Human skin fibroblasts, both DNA repair deficient (xeroderma pigmentosum group A: XPA) and DNA repair normal have been co-transformed with a chimeric gene construct containing human CYP1A1 coding sequences controlled by the cadmium (Cd) ion inducible mouse metallothionein-I promoter and pRSV-NEO, a dominant selectable marker for G418 resistance. Individual G418 resistant colonies were cloned and analyzed for Cd inducible CYP1A1 activity. Six clones of DNA repair deficient cells and five clones of DNA repair proficient cells have been isolated which express Cd inducible CYP1A1. Benzo[a]pyrene-trans-7,8-diol (BPD) is cytotoxic in Cd induced CYP1A1 expressing cells. The cytotoxicity can be inhibited by 10 microM alpha-napthoflavone. Differential cytotoxicity between the DNA repair deficient and proficient CYP1A1 expressing transformants is observed. BPD is cytotoxic to Cd induced CYP1A1 expressing XPA cells at > 10-fold lower doses than it is to Cd induced CYP1A1 expressing DNA repair normal cells. These data indicate that BPD is metabolized to a DNA damaging agent by induced CYP1A1. In contrast, benzo[a]pyrene-trans-7,8-diol-9,10-epoxide added to the media is only slightly more cytotoxic to DNA repair deficient than to proficient cells regardless of CYP1A1 expression. These studies demonstrate the usefulness of the CYP1A1 transformed fibroblasts in examining the cytotoxic effects of benzo[a]pyrene metabolites and suggest the future usefulness in examining the toxic effects of polycyclic aromatic hydrocarbons and other xenobiotics bioactivated by CYP1A1.
 ...
PMID:Expression of human cytochrome P450 1A1 in DNA repair deficient and proficient human fibroblasts stably transformed with an inducible expression vector. 835 49