Animal and human studies on aryl hydrocarbon hydroxylase (AHH) have demonstrated wide inter-individual variation. First attempts to link this variation to the susceptibility to certain cancers have been successful in mice but remained inconclusive in man. In a new approach, saliva antipyrine half-lives and metabolic clearance rates have been used to assess individual rates of benzo]a]pyrene metabolism in human subjects. Saliva antipyrine half-lives and metabolic clearance rates have been measured in 57 patients with lung cancer, 90% of whom had quit smoking more than three months prior to the test, 57 cancer-free matched controls, and 59 healthy smoking controls. The mean antipyrine half-life was significantly shorter (P less than 0.001) in lung cancer patients when compared with the cancer-free matched control group, but differed little from that of the smoking group (P less than 0.05). The data support the previous observation than lung cancer patients have increased oxidation rates which, in addition to smoking, might have predisposed them to developing lung cancer.

The metabolism of antipyrine and oxazepam has been measured in twelve healthy subjects. Antipyrine, an analgesic and antipyretic drug, is extensively metabolized by oxidation at various sites and oxazepam, a benzodiazepine, is almost exclusively metabolized by conjugation with glucuronic acid. Comparing the plasma clearance rates and the plasma half lives of the two drugs, correlation coefficients of r = 0.766 (P less than 0.01) and r = 0.966 (P less than 0.01) have been obtained. The data suggests that in man the processes of oxidation and glucuronidation are linked by a common control which regulates the metabolic rates of the two reactions.

The plasma elimination rates of phenacetin, acetanilide and theophylline have been determined in 32 healthy subjects in an effort to find drugs resembling in their metabolism the carcinogen benzo(a)pyrene. The plasma half-lives and metabolic clearance rates of the three drugs were correlated with the inducibilities of aryl hydrocarbon hydroxylase (AHH) in mitogen-stimulated lymphocytes and the plasma half-lives and metabolic clearance rates of antipyrine determined in previous studies. Statistically significant correlations were found between the half-lives and metabolic clearance rates of phenacetin, acetanilide and theophylline and the AHH ratios except for the metabolic clearance rates of phenacetin which did not correlate. The correlations of the three drugs with the half-lives and metabolic clearance rates of antipyrine were equally good. Of all the drugs tested thus far for similarity in metabolism to benzo(a)pyrene, antipyrine showed the best association followed closely by theophylline.

The metabolism of antipyrine (AP) has been investigated in 15 healthy subjects by relating the saliva AP elimination rates to the urinary excretion rates of 4-hydroxyantipyrine (AP-40H), 3-hydroxymethylantipyrine (AP-CH2OH) and N-demethylantipyrine (AP-NH2). Highly significant correlation coefficients have been obtained for AP-40H (r = 0.94). AP-CH2OH (r = 0.85) and for AP-NH2 (r = 0.86). While little interindividual variation occured in the urinary concentrations of AP-4OH and AP-CH2OH, two-fold variation was found for AP-NH2. The ratios of the three metabolites were highly constant over a period of several months in some subjects but slightly variable in others indicating their control by genetic and environmental factors.

Lung cancer is one of the leading causes of cancer deaths in most Western countries. In the United States it accounts for 33% of the cancer deaths in males and 11% of the cancer deaths in females. More males die from lung cancer than from the four next common cancer sites combined, i. e., colon, prostate, pancreas, and stomach cancer. In females, lung cancer holds third place in cancer deaths, preceded only by breast and colon cancer (Silverberg, 1977). Of all the common cancers it is the one most clearly associated with environmental agents, the most notable of which is cigarette smoking.

Phenobarbital and antipyrine half-lives were measured in 31 subjects. A high correlation ( r = 0.87) was found for the plasma elimination rates of the two drugs, suggesting the same or a similar route or a common regulatory control of their metabolism. The half-lives of phenobarbital and antipyrine also correlated highly with the aryl hydrocarbon hydroxylase (AHH) inducibilities in mitogen-stimulated lymphocytes of the same individuals. In the second part of the study, plasma antipyrine half-lives were measured in 22 subjects after a single oral dose of 18 mg/kg, and the AHH inducibilities were determined in their cultured lymphocytes. After 7 days on phenobarbital at aryl hydrocarbon hydroxylase inducibilityadjusted doses ranging between 1.0 and 2.0 mg/kg daily, the antipyrine half-lives were measured again and the percentage of decrease between the initial and second antipyrine half-lives was determined. Shortening of the plasma half-lives occurred in all subjects to various degrees, ranging between 13.3 and 30.6%. However, under our experimental conditions in which the dose of phenobarbital was adjusted to the individual rates of metabolism of the inducing agent, no relationship could be found between the initial antipyrine half-life and the percentage of shortening of its plasma half-life, such as had been reported by several authors.

A strong correlation was found in a carefully selected homogenous population (n = 57) between antipyrine plasma half-life and the percent induction of aryl hydrocarbon hydroxylase by 3-methylcholanthrene in mitogen-stimulated lymphocytes from the same individual. The correlation coefficient of r = 0.923 indicates that antipyrine and benzo[a]pyrene share one or several common determinants that are responsible for the observed interindividual variation in the oxidation rates of the two compounds. When a heterogenous population (n = 80) was studied, the above correlation was not found (r = 0.425).

A high correlation was observed between the aryl hydrocarbon hydroxylase activities in short-term lymphocyte cultures of 23 individuals and their plasma half-lives of antipyrine and phenylbutazone. Individuals with low inducibility of aryl hydrocarbon hydroxylase activities had very long plasma half-lives of antipyrine and phenylbutazone, whereas subjects with high inducibility of aryl hydrocarbon hydroxylase activites had relatively short plasma half-lives. Individuals with intermediate aryl hydrocarbon hydroxylase activities displayed intermediate half-lives for both drugs. The observed correlation indicates determinants which are common to the elimination of antipyrine or phenylbutazone, and aryl hydrocarbon hydroxylase metabolism of hydrocarbons. The differences in rates of drug elimination are probably due to genetic differences and may have pharmacological and therapeutic significance.