Steroid synthesis requires cholesterol derived from de novo synthesis or plasma lipoproteins. Low density lipoproteins appear to be the major contributor of cholesterol for steroid synthesis in man. Patients with disorders of low density lipoproteins or the low density lipoprotein receptor have reduced cortisol production in response to ACTH. Therapeutic agents designed to lower plasma cholesterol could, therefore, adversely affect steroid hormone production. Lovastatin (mevinolin) is a new hypolipidemic agent which blocks cholesterol synthesis by competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. In beagle dogs, lovastatin at 40-180 times the clinically effective dose in man, has been associated with an increase in spontaneous testicular atrophy. Accordingly, the effect of lovastatin on testicular function and lipoprotein levels was studied in 16 hyperlipidemic men in a randomized, double blind, cross-over study with another hypolipidemic agent, neomycin. Serum testosterone, PRL, LH, and FSH; LHRH-stimulated LH and FSH concentrations; and testicular size were measured, and semen analyses were made. We found no evidence that lovastatin had adverse effects on testicular function despite significant alterations in plasma lipoprotein concentrations.

No abstract

No abstract

The human skin cancer-prone disease xeroderma pigmentosum variant (XPV) results from a mutation in RAD30, which encodes the novel lesion bypass DNA polymerase η. XPV cells are characterized by delayed completion of DNA replication and increased mutagenesis following UV irradiation. In cell-free extracts of XPV lymphoblasts, functional DNA polymerase η is required for the complete replication of a doublestranded plasmid containing either a single (6-4) photoproduct or a cyclobutane pyrimidine dimer (CPD), the major mutagenic UV-induced lesion. In cultured XPV cells, replication arrest activates downstream signalling pathways, leading to hyperphosphorylation of the 34-kDa subunit of the trimeric single-stranded DNAbinding protein, RPA (replication protein A). Many of the RAD30 mutations identified in XPV cells result in truncation and inactivation of DNA polymerase η. To examine whether polymorphisms in the RAD30 gene that result in altered polymerase η function, rather than enzyme inactivation, might contribute to individual susceptibility to skin cancer, methods to screen for sequence changes in the RAD30 gene in human genomic DNA have been developed.