Cigarette smoke condensate induces cytochromes P450 and aldo-keto reductases in oral cancer cells

Abstract

Our objective is to identify molecular factors which contribute to the increased risk of smokers for oral squamous cell carcinoma (OSCC). In the present study, we investigated the effects of cigarette smoke condensate (CSC) on gene expression profiles in different human oral cell phenotypes: normal epidermal keratinocytes (NHEK), oral dysplasia cell lines (Leuk1 and Leuk2), and a primary oral carcinoma cell line (101A). We determined differential gene expression patterns in CSC-exposed versus non-exposed cells using high-density microarray RNA expression profiling and validation by quantitative real-time RT-PCR. A set of 35 genes was specifically up- or down-regulated following CSC treatment (25microg/ml for 24h) by at least 2-fold in any one cell type. Notably, five genes of the cytochrome P450 (CYP1A1, CYP1B1) and aldo-keto reductase (AKR1C1, AKR1C3, AKR1B10) families were highly increased in expression, some of them 15- to 30-fold. The timing and extent of induction for these genes differed among the four cell phenotypes. A potential biological interaction network for the CSC response in oral cells was derived from these data, proposing novel putative response pathways. These CSC-responsive genes presumably participate in the prevention or repair of carcinogen-induced DNA damage in tobacco-related oral carcinogenesis, and may potentially be exploited for determining the severity of exposure and for correcting mutagenic damage in exposed tissues of the oral cavity.

Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate

“…6) and inhibiting some transporters like OATP1B1, OATP1B3, OCT1 and MATE1 (Fig. 1B) are similar to those used in previous studies with cultured cells, including human hepatic cells (Fields et al 2005;Nagaraj et al 2006;Xiao et al 2015); they also up-regulated the drug metabolizing enzymes CYP1A1 and CYP1B1, that, together with other AhR targets such as CYP1A2, constitute key targets induced by smoking in humans (Chang et al 2003;Dobrinas et al 2011;Thum et al 2006) and are in the range of CSC concentrations (20 to 120 µg/mL) previously hypothesized to be relevant for human smokers (Gao et al 2005). On the other hand, 10-40 µg/mL CSC corresponds to 0.768-3.072 µg/mL (4.73-18.92 µM) nicotine, when considering that CSC contains 7.68 % (weight/weight) nicotine (Eldridge et al 2015), and such nicotine concentrations are much higher than those (25 to 444 nM) commonly described in smoker blood (Russell et al 1980).…”

“…CSC, supplied by Murty Pharmaceuticals (Lexington, KY), was prepared by smoking University of Kentucky's 3R4F standard research cigarettes on a Federal Trade Commission smoke machine (Nagaraj et al 2006). Smoke particulates were collected on a glass fiber filter.…”

Genomics of Smoking Exposure and Cessation: Lessons for Cancer Prevention and Treatment

“…Zhang and colleagues provide further in vivo evidence that many of these genes are down-regulated in persons who reported quitting smoking at least 1 year before the assessment (CYP1B1, AKR1C1, AKR1C2, AKR1B10, and ALDH3A1). Many of these same genes were previously shown to be overexpressed in oral cancer cells exposed to tobacco smoke condensate (8), in bronchial epithelial cells of smokers, and in patients' non-small cell lung carcinoma cells (9,10). The effects are also consistent with the effects of smoking on the airway transcriptome (11,12).…”

The Contribution of Matrix Metalloproteinase-8 Promoter Polymorphism to Oral Cancer Susceptibility

“…This is the first study to reveal an interaction between MMP1 1607 genotype and cigarette smoking on the susceptibility to oral cancer. Long-term tobacco smoking and areca chewing have been shown to contribute to etiology of oral cancer development (9,10,(41)(42)(43)(44). The results showed that gene-environment interaction was not obvious between MMP-8 genotypes and personal risk behaviors, alcohol drinking, cigarette smoking or areca chewing.…”