A form of cytochrome P450 in man, orthologous to form d in the rat, catalyses the O‐deethylation of phenacetin and is inducible by cigarette smoking.

Abstract

1. In previous studies (Boobis et al., 1985b) it was shown that a monoclonal antibody (MAb 3/4/2), raised against rat cytochrome P450 form c, reacts with an isoenzyme(s) of cytochrome P450 in human liver. It was predicted that the epitope with which this antibody reacts should be present on both isoenzymes of the P450IA gene sub‐family (the orthologues of forms c and d) in man (Edwards et al., 1987). 2. This antibody was used to probe 45 different samples of human liver, by the technique of Western blotting. With one exception, all of the samples contained immunoreactive protein, a single band at Mr 54,000 (orthologous to rat form d), which ranged in content from less than 0.5 to 33.5 pmol mg‐1 microsomal protein. The content of the human orthologue of form c was below 0.5 pmol mg‐1, the limit of detection of the assay. 3. Thirteen of the samples were from patients of known smoking status. Immunoreactive P450 content was 3.5‐fold higher, and phenacetin O‐deethylase activity was four‐fold higher, in the smokers than in the non‐smokers. 4. There was a highly significant correlation between the amount of immunoreactive cytochrome P450 and the high affinity component of phenacetin O‐deethylase activity in both smokers and non‐smokers. 5. It is concluded that the high affinity component of phenacetin O‐deethylase activity in man is catalysed by the orthologue of rat cytochrome P450d, and that this isoenzyme is inducible by cigarette smoking. 6. In a number of previous publications it has been suggested that there is an association between the poor metaboliser (PM) phenotype for debrisoquine and impaired phenacetin O‐deethylation. In the present study it was shown that not all subjects PM for debrisoquine are poor metabolisers of phenacetin.

Polymorphisms for Aromatic Amine Metabolism in Humans: Relevance for Human Carcinogenesis

“…Moreover, probit analysis and frequency plots show apparent trimodal distributions with different cut-off points in smokers and nonsmokers. These data provide strong evidence that CYP1A2 is induced in humans by cigarette smoking and are consistent with results from previous studies that show that smoking increases caffeine clearance (39), phenacetin O-deethylation (40) and levels of CYP1A2 in human liver microsomes (33,34 …”

“…Each of these CYPs appears to exhibit wide interindividual variation, and evidence for their inducibility by drugs and by environmental and dietary factors has been reported. Whether or not genetic polymorphisms exist is as yet unknown, although an apparently bimodal distribution for CYP1A2 in liver microsomes has been described (33,34). Since the identification of caffeine 3-demethylation (CYP1A2), chlorzoxazone 6-hydroxylation (CYP2E1), and cortisol 6I8-hydroxylation (CYP3A4) as selective assays for these CYPs (31), studies are currently in progress in several laboratories on the application of phenotyping (and genotyping) methods to human populations.…”

Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine.

“…IMX is further oxidized to 1-methyluric acid (1MU) by the cytoplasmatic enzyme xanthine oxidase [12]. There is strong direct and indirect evidence that CYP1A2 is involved in all the major pathways of theophylline metabolism [6,[13][14][15][16]. The inducing effect of cigarette smoking is greatest on the two N-demethylation pathways and CYP1A2 is believed to catalyze about 80-90% of the N-demethylations and about 50% of the 8-hydroxylation in vitro [17].…”

“…Indeed fluoxetine, its of 1.8 to 8.2 JIM [1][2][3]. However, fluvoxamine is a Correspondence: Dr Birgitte Buur Rasmussen, Department of Clinical Pharmacology, Institute of Medical Biology, Odense University, Winsl0vparken 19, DK-5000 Odense C, Denmark potent inhibitor of the O-deethylation of phenacetin [4] (Ki~0.12 to 0.24 gM) and of the N-demethylation of imipramine [1] (Ki~0.14 JM), two well-established marker reactions for cytochrome P4501A2 (CYP1A2) function in human liver microsomes [5][6][7]. Fluvoxamine inhibition of P450 isoforms other than CYP1A2 and CYP2D6 has not previously been investigated.…”

Cytochrome P450 1A2 Polymorphisms, Coffee Consumption and Impaired Glucose Metabolism in Japanese Men

“…This effect modification was more evident in current smokers. It is documented that cigarette smoking induces CYP1A2 activity in humans [22,23], and both CYP1A2*1C and CYP1A2*1F affect the inducibility of the enzyme [15,17]. Thus it is of interest whether the interactions between these polymorphisms and coffee on impaired glucose metabolism may differ by smoking status.…”