1 Furafylline (1,8-dimethyl-3-(2'-furfuryl)methylxanthine) is a methylxanthine derivative that was introduced as a long-acting replacement for theophylline in the treatment of asthma. Administration of furafylline was associated with an elevation in plasma levels of caffeine, due to inhibition of caffeine oxidation, a reaction catalysed by one or more hydrocarbon-inducible isoenzymes of P450. We have now investigated the selectivity of inhibition of human monooxygenase activities by furafylline. 2 Furafylline was a potent, non-competitive inhibitor of high affinity phenacetin 0-deethylase activity of microsomal fractions of human liver, a reaction catalysed by P450IA2, with an IC50 value of 0.07 FLM.3 Furafylline had either very little or no effect on human monooxygenase activities catalysed by other isoenzymes of P450, including P4501ID1, P4501IC, P450IIIA. Of particular interest, furafylline did not inhibit P4501A1, assessed from aryl hydrocarbon hydroxylase activity of placental samples from women who smoked cigarettes. 4 It is concluded that furafylline is a highly selective inhibitor of P450IA2 in man. 5 Furafylline was a potent inhibitor of the N3-demethylation of caffeine and of a component of the Ni-and N7-demethylation. This confirms earlier suggestions that caffeine is a selective substrate of a hydrocarbon-inducible isoenzyme of P450 in man, and identifies this as P450IA2. Thus, caffeine N3-demethylation should provide a good measure of the activity of P450IA2 in vivo in man. 6 Although furafylline selectively inhibited P450IA2, relative to P4501A1, in the rat, this was at 1000-times the concentration required to inhibit the human isoenzyme, suggesting a major difference in the active site geometry between the human and the rat orthologues of P50IA2.

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.

1. In the safety evaluation of drugs and other chemicals it is important to evaluate their possible inducing and inhibitory effects on the enzymes of drug metabolism. 2. While many similarities exist between species in their response to inducers and inhibitors, there are also important differences. Possible mechanisms of such variation are considered, with particular reference to the cytochrome P-450 system. 3. Differences in inhibition may be due to differences in inhibitory site of the enzyme involved, which is not always the active site of the enzyme, in competing pathways or in the pharmacokinetics of the inhibitor. 4. Differences in induction could be due to differences in the nature of the induction mechanism, in the isoenzyme induced, in tissue- or age-dependent regulation, in competing pathways for the substrate or its products, or in the pharmacokinetics of the inducing agent. 5. Examples of each of these possible differences are considered, often from our own work on the P450 IA subfamily, and results in animals are compared with those in humans, where possible. 6. At present, the differences between species in their response to inducers and inhibitors make extrapolation to humans from the results of animal studies difficult, so that ultimately such effects should be studied in the species of interest, humans.

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A 2-wk course of rifampicin orally (600 mg/day) in 8 male subjects resulted in a consistent fall in plasma 25-hydroxycholecalciferol (25-OHD) levels of around 70%, accompanied by increased oxidation of antipyrine and 6 beta-hydroxycortisol (indicative of hepatic enzyme induction). Plasma levels of 1,25-dihydroxycholecalciferol, parathyroid hormone, and calcitonin were not altered. The fall in 25-OHD may represent the earliest lesion of drug-induced osteomalacia.