Cytochrome P450 1b1 in polycyclic aromatic hydrocarbon (PAH)-induced skin carcinogenesis: Tumorigenicity of individual PAHs and coal-tar extract, DNA adduction and expression of select genes in the Cyp1b1 knockout mouse

Abstract

FVB/N mice wild-type, heterozygous or null for Cyp 1b1 were used in a two-stage skin tumor study comparing PAH, benzo[a]pyrene (BaP), dibenzo[def,p]chrysene (DBC), and coal tar extract (CTE, SRM 1597a). Following 20 weeks of promotion with TPA the Cyp 1b1 null mice, initiated with DBC, exhibited reductions in incidence, multiplicity, and progression. None of these effects were observed with BaP or CTE. The mechanism of Cyp 1b1-dependent alteration of DBC skin carcinogenesis was further investigated by determining expression of select genes in skin from DBC-treated mice 2, 4 and 8 h post-initiation. A significant reduction in levels of Cyp 1a1, Nqo1 at 8 h and Akr 1c14 mRNA was observed in Cyp 1b1 null (but not wt or het) mice, whereas no impact was observed in Gst a1, Nqo 1 at 2 and 4 h or Akr 1c19 at any time point. Cyp 1b1 mRNA was not elevated by DBC. The major covalent DNA adducts, dibenzo[def,p]chrysene-(±)-11,12-dihydrodiol-cis and trans-13,14-epoxide-deoxyadenosine (DBCDE-dA) were quantified by UHPLC-MS/MS 8 h post-initiation. Loss of Cyp1 b1 expression reduced DBCDE-dA adducts in skin but not to a statistically significant degree. The ratio of cis-to trans-DBCDE-dA adducts was higher in skin than other target tissues such as spleen, lung and liver (oral dosing). These results document that Cyp 1b1 plays a significant role in bioactivation and carcinogenesis of DBC in a two-stage mouse skin tumor model and that loss of Cyp 1b1 has little impact on tumor response with BaP or CTE as initiators.

Cyclodextrin-functionalized mesostructured silica nanoparticles for removal of polycyclic aromatic hydrocarbons

“…On contact with body tissues, they undergo metabolic activation to reactive epoxide compounds through an enzymatic oxidation pathway initiated by cytochrome P450 (CYP), and the formed reactive metabolites are capable of binding to nucleotides on a cellular DNA, forming PAH-DNA adducts. If not repaired, these adducts may induce mutations in oncogenes and suppression genes, eventually leading to the transformation of a normal cell into a cancer cell [3][4][5]. In vivo studies with mice demonstrated mutagenicity of PAHs; for example, pregnant mice exposed to benzo(a)pyrene (B [a]p) for 10 days showed the effects of birth defects [6,7].…”

Inhibition of Carcinogen-Activating Cytochrome P450 Enzymes by Xenobiotic Chemicals in Relation to Antimutagenicity and Anticarcinogenicity

“…These cell lines express Cyp1a1 protein at significant levels, but not Cyp1b1 protein, indicating that Cyp1b1 has a major role in activating 7,12-DMBA in vivo (32). The Cyp1b1-null mice have also been reported to be reduced in formation of ovarian cancers at a low dose of 7,12-DMBA (33), ovarian and skin tumors caused by DB[a,l]P (34,35), and skin tumors by dibenzo[def,p]chrysene (DB[a,l]P) (36). Disruption of Cyp1b1-null mice has been shown to be reduced in pre-B cell apoptosis (37), bone marrow cytotoxicity (38), and spleen cell immunotoxicity (39) by treatment with 7,12-DMBA.…”

Gene polymorphism of cytochrome P450 significantly affects lung cancer susceptibility

“…Maurya et al reported that polymorphisms of drug metabolizing CYPs showed modest associations with head and neck squamous cell carcinoma risk . Genetic polymorphisms have been reported for CYPs involved in the metabolic activation of polycyclic aromatic hydrocarbons (PAHs) and tobacco‐specific nitrosamines, both of which are wide spreading environmental procarcinogens that induce LC and skin carcinoma . However, Kiyohara C et al have found no significant association between the genetic polymorphism of enzymes involved in xenobiotic metabolism and the risk of LC …”

“…17 Genetic polymorphisms have been reported for CYPs involved in the metabolic activation of polycyclic aromatic hydrocarbons (PAHs) and tobaccospecific nitrosamines, 18,19 both of which are wide spreading environmental procarcinogens that induce LC and skin carcinoma. [20][21][22] However, Kiyohara C et al have found no significant association between the genetic polymorphism of enzymes involved in xenobiotic metabolism and the risk of LC. 23 To sum up, the correlation of CYPs polymorphisms and LC risk is contradictory and inconclusive due to the diversity of ethnicity and sample size in study groups.…”