Publications

Chronic granulomatous disease is characterized by recurrent infections that result from an inability of phagocytes to kill organisms effectively. We describe a patient with this disease who developed aspergillus pneumonia after shoveling moldy cedar wood chips. Despite aggressive therapy, the patient's condition deteriorated and he died. At autopsy, the lungs revealed diffuse granulomas, all of the same age, with aspergillus organisms confined to the granulomas. We propose the term "microgranulomatous aspergillosis" for this response, which does not conform to the commonly described aspergillus syndromes. We conclude that susceptible immunosuppressed patients should be advised to avoid occupational situations where high spore concentrations are generated.

Testosterone (T) 6 beta-hydroxylase (6 beta-OHase) is a well-recognized functional marker of rat liver cytochrome P450 3A (P450 3A) isozymes. Pretreatment of rats with inducers or specific or nonspecific inhibitors of P450 3A isozymes is associated not only with stimulation or inhibition of hepatic microsomal T 6 beta-OHase activity but also with parallel changes in the corresponding T 2 beta-, 15 beta-, and 18-OHase activities and T 4,6-diene formation. At the time these studies were conducted, no fully functionally active rat hepatic P450 3A isozymes had been isolated. To determine whether each of these activities was due to a single P450 3A isozyme, or whether multiple isozymes contributed to these activities, we specifically synthesized two thiotestosterone (6 beta- and 2 beta-SHT) analogues as potential mechanism-based inactivators of rat liver T 6 beta- and 2 beta-OHases. In addition, to assess their relative stereoselectivity, 2 alpha-SHT was also included as a control. Our studies revealed that although all three thiosteroids were excellent suicide substrates of P450 3A isozymes, they inactivated these T OHases differentially. Such differential inactivation and determination of the kinetic parameters of inactivation allowed the functional classification of rat hepatic P450 3A isozymes into at least two and possibly three categories: (i) forms (catalyzing 4,6-diene and 6 beta-OHT formation but with characteristically low 6 beta/2 beta-OHase ratios) highly susceptible to inactivation by SHTs; (ii) forms (catalyzing T 6 beta-, 2 beta-, 15 beta-, and 18-hydroxylations with high 6 beta-/2 beta-OHase ratios) moderately susceptible to the SHTs; and (iii) forms somewhat resistant to inactivation, at least at the SHT concentrations tested. Although no specific T OHase could be ascribed to a single P450 3A isozyme, it appears that each of these P450s catalyzed such T regiohydroxylations, albeit at considerably different extents. Furthermore, our studies also revealed that 2 alpha-SHT preferentially inactivated P450 3A forms but surprisingly failed to inactivate rat hepatic P450 2C11, thereby confirming the rather high substrate promiscuity of the P450 3A family of isozymes.